Nitrogen-containing heterocyclic compound small-molecule inhibitor and use thereof

Abstract

Provided in the present disclosure is a compound as represented by formula (I), which compound exhibits a good PCSK9 inhibitory activity and can be used as a PCSK9 inhibitor for lowering blood lipids.

Description

Small molecule inhibitors of nitrogen-containing heterocyclic compounds and their applications

[0001] This application requests the following:

[0002] Priority rights to the earlier application filed with the China National Intellectual Property Administration on January 27, 2025, with patent application number 202510126141.6 and entitled "Preparation method and application of lipid-lowering nitrogen-containing heterocyclic compound small molecule inhibitor";

[0003] Priority rights to the earlier application filed with the China National Intellectual Property Administration on June 20, 2025, with patent application number 202510835691.5 and title "Preparation method and application of lipid-lowering nitrogen-containing heterocyclic compound small molecule inhibitor";

[0004] Priority rights to the earlier application filed with the China National Intellectual Property Administration on October 17, 2025, with patent application number 202511489392.7 and title "Preparation method and application of lipid-lowering - nitrogen-containing heterocyclic compound small molecule inhibitor";

[0005] Priority rights to the earlier application filed with the China National Intellectual Property Administration on November 28, 2025, with patent application number 202511778566.1 and title "Preparation method and application of lipid-lowering nitrogen-containing heterocyclic compound small molecule inhibitor";

[0006] The full text of the prior application is incorporated herein by reference. Technical Field

[0007] This invention belongs to the pharmaceutical field, specifically relating to a small molecule inhibitor of nitrogen-containing heterocyclic compounds and its application. Background Technology

[0008] PCSK9 is a liver-derived secretory protein that binds to the extracellular domain of LDLR; however, PCSK9's degradation of LDLR is intracellular. PCSK9 does not require kinase catalytic activity to influence LDLR conversion; kinase catalytic activity cannot guide the receptor-carrying complex to the lysosomes where the complex is degraded or inhibit the complex's circulation. As a neuronal apoptosis-regulating enzyme, PCSK9 not only participates in liver regeneration and regulates neuronal apoptosis but also affects LDL internalization by reducing the amount of LDLR on hepatocytes, leading to impaired LDL clearance from the blood and resulting in hypercholesterolemia. Studies have shown that PCSK9 levels are significantly correlated with cholesterol, ox-LDL, and triglycerides. As a serine protease, PCSK9, in addition to degrading LDLR and increasing blood LDL levels, has various other biological functions, such as participating in nervous system development, neuronal apoptosis, and regulating sodium channels and pancreatic islet cell function. The process of PCSK9 production begins with the synthesis of PCSK9 proenzyme in the endoplasmic reticulum. PCSK9 proenzyme then undergoes an autocatalytic reaction in the endoplasmic reticulum or Golgi apparatus, cleaving to release a propeptide, forming a mature protease, which is immediately secreted into the blood. By regulating LDLR, it maintains the homeostasis of plasma lipids and can affect plasma cholesterol levels.

[0009] However, PCSK9 inhibitors may cause abnormal liver function, manifesting as elevated transaminases, jaundice, ascites, and in severe cases, may develop into cirrhosis or even liver failure. They may also affect the number and activity of low-density lipoprotein receptors, leading to elevated serum total cholesterol and low-density lipoprotein cholesterol levels, increasing the risk of cardiovascular disease. Therefore, there is a need to develop more effective and safer lipid-lowering drugs. Summary of the Invention

[0010] To address the aforementioned technical problems, this disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0011] E2-L-E1-XAYG (I)

[0012] Wherein, A is selected from unsubstituted or arbitrarily substituted by one, two or more Rs. a The following groups are substituted: C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10 quinone heteroaryl; each R a They are either the same or different, and are independently selected from halogens, OH, CN, and C. 1-10 alkyl;

[0013] X does not exist or is selected from single bonds, N(R) x ), S, C(R) x (R) x ); Each R xThey may be the same or different, and are independently selected from H, halogens, OH, CN, and C. 1-10 Alkyl group; when X is absent, A and E1 are screwed together to form a helical ring;

[0014] Y is selected from S, without substitution, or optionally by one, two, or more R. y The following groups are substituted: NH, NHC(O), NHC(O)O, -CH2NH-, -CH2CH2NH-; each R y They are either the same or different, and are independently selected from halogens, OH, CN, and C. 1-10 Alkyl; or, two Rs y The atoms connected to each other form C 3-10 cycloalkyl;

[0015] E1 is selected from unsubstituted or optionally by one, two or more R... E1 The following groups are substituted: 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10 quinone heteroaryl; each R E1 They are either the same or different, and are independently selected from halogens, OH, CN, and C. 1-10 alkyl;

[0016] E2 is selected from OH, unsubstituted, or optionally surrounded by one, two, or more R groups. E2 The following groups are substituted: C 1-10 Alkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10 membered heteroaryl, amino; each R E2 They are either the same or different, and are independently selected from halogens, oxometalates (=O), OH, CN, C(O)OH, C 1-10 Alkyl, Halogenated C 1-10 Alkyl, C 3-10 cycloalkyl, C 6-10 Aryl, Halogenated C 6-10 Aryl, Halogenated C 1-10 Alkoxy, C 1-10 Alkoxy-C 6-10 Aryl-C 1-10 Alkyl, C 3-10 cycloalkyl-NH-;

[0017] L is selected from single bond, -N(R) L )-、-C(O)C(R L (R) L )-、-C(O)N(R L )-、-C(R L (R) L -; each R L They may be the same or different, and are independently selected from H, without substitution, or optionally by one, two, or more R. L1The following groups are substituted: C 1-10 Alkyl, C 3-10 cycloalkyl, C 3-10 Cycloalkenyl, C 6-10 Aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclic; each R L1 They are either the same or different, and are independently selected from halogens, oxometalates (=O), and carbon atoms. 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 1-10 Alkyl-C 3-10 cycloalkyl;

[0018] Or, two Rs L The atoms connected to each other form C 3-10 cycloalkyl groups, 3-10 membered heterocyclic groups;

[0019] G is selected from unsubstituted or optionally by one, two or more Rs. g The following groups are substituted: C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10 quinone heteroaryl; each R g They may be the same or different, and are independently selected from halogens, OH, CN, oxo (=O), and C. 1-10 Alkyl, C 1-10 Alkoxy, halogenated C 1-10 Alkyl, Halogenated C 1-10 Alkoxy, C 1-10 Alkyl-NH-, C 3-10 cycloalkyl-NH-, halogenated C 3-10 cycloalkyl-NH-, C 1-10 Alkyl-NHC(O)-, C 1-10 Alkyl-C(O)NH-;

[0020] According to embodiments of this disclosure, A is selected from unsubstituted or optionally replaced by one, two or more R. a The following groups are substituted: C 3-8 Cycloalkyl, 5-9 membered heterocyclic groups, C 6-9 Aryl, 5-6 quinone heteroaryl;

[0021] According to embodiments of this disclosure, A is selected from unsubstituted or optionally replaced by one, two or more R. a The following groups may be substituted: cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[3.1.0]hexyl, spiro[2.4]heptyl, bicyclo[3.2.0]heptyl, 2-azaspiro[3.4]octyl, phenyl, pyridyl, 2,3-dihydro-1H-indenyl;

[0022] According to the implementation scheme of this disclosure, each R aThey may be the same or different, and are independently selected from halogens (e.g., F), OH, CN, C. 1-6 alkyl;

[0023] According to the implementation scheme of this disclosure, A is selected from... And when X does not exist

[0024] At that time, A was selected from

[0025] According to the implementation scheme of this disclosure, A is selected from... And when X does not exist, A is selected from

[0026] According to the embodiments of this disclosure, X is selected from single bonds, N(R) x ), S, C(R) x (R) x ); Each R x They are either the same or different, and are independently selected from H, OH, CN, and C. 1-6 Alkyl groups (e.g., methyl groups);

[0027] According to the embodiments of this disclosure, X is selected from single bonds, NH, S, (For example ), (For example ).

[0028] According to the implementation scheme of this disclosure, Y is selected from NH, S, NHC(O), NHC(O)O,

[0029] According to the implementation scheme of this disclosure, each R y Same or different, selected independently from C 1-6 Alkyl (e.g., methyl); or, two Rs y The atoms connected to each other form C 3-6 Cycloalkyl groups (e.g., cyclopropyl);

[0030] According to the implementation scheme of this disclosure, Y is selected from NH, S, NHC(O), NHC(O)O, (For example ),

[0031] According to embodiments of this disclosure, E1 is selected from unsubstituted or optionally replaced by one, two or more R. E1 The following groups are substituted: 6-9 membered heterocyclic groups, C 6-8 Aryl, 5-6 quinary heteroaryl, 9-10 quinary heteroaryl;

[0032] According to embodiments of this disclosure, E1 is selected from unsubstituted or optionally replaced by one, two or more R. E1 The following groups are substituted: pyridinyl, pyridazinyl, thiazolyl, oxazolyl, phenyl, benzimidazolyl, 2,3-dihydro-1H-pyrrolo[3,2-b]pyridinyl, indolinel;

[0033] According to the implementation scheme of this disclosure, E1 is selected from...

[0034] According to the implementation scheme of this disclosure, each R E1 They may be the same or different, and are independently selected from halogens (e.g., F, C). 1-6 alkyl;

[0035] According to the implementation scheme of this disclosure, E1 is selected from... (For example ), (For example ), And when X does not exist, E1 is selected from

[0036] According to embodiments of this disclosure, E2 is selected from OH, unsubstituted, or optionally substituted with one, two, or more R groups. E2 The following groups are substituted: C 1-6 Alkyl, 4-8 membered heterocyclic, 9-10 membered heterocyclic, C 6-8 Aryl, 5-6 quinary heteroaryl, 8-10 quinary heteroaryl;

[0037] According to embodiments of this disclosure, E2 is selected from OH, unsubstituted, or optionally substituted with one, two, or more R groups. E2 The following groups are substituted: methyl, 1,2-dihydropyridyl, pyrrolyl, imidazole, phenyl, 2,3-dihydro-1H-imidazolyl, aziridine, aziridine-butenyl, tetrahydropyrrolyl, indolinel, Indolyl, 1H-pyrrolo[3,2-b]pyridyl, pyrazolyl, 1H-pyrrolo[2,3-b]pyridyl, 2H-indazoleyl, thiazolyl, triazolyl, dihydropyrrolyl, 1H-pyrazololo[3,4-b]pyridyl, 7H-pyrrolo[2,3-c]pyridazinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, 1H-pyrrolo[3,4-d]pyrimidinyl, indololinyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine, 6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidinyl, morpholinyl, piperazinyl, piperidinyl, amino, oxazolyl, isoxazolyl, oxadiazolyl, furanyl

[0038] According to the implementation scheme of this disclosure, each R E2 They are either the same or different, and are independently selected from halogens, oxometalates (=O), C(O)OH, CN, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-6 cycloalkyl, C 6-8 Aryl, Halogenated C 6-8 Aryl, Halogenated C 1-6 Alkoxy, C 1-6 Alkoxy-C 6-8 Aryl-C 1-6 Alkyl, C 3-6 cycloalkyl-NH-;

[0039] According to the implementation scheme of this disclosure, each R E2 They are either the same or different, and are independently selected from F, oxo(=O), C(O)OH, CN, methyl, difluoromethyl, phenyl, 4-methoxybenzyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, trifluoromethoxy, difluoromethoxy, cyclopropyl, cyclopropyl-NH-, 3-fluorophenyl, 4-fluorophenyl, 3,4-difluorophenyl;

[0040] According to the embodiments of this disclosure, E2 is selected from OH, methyl, difluoromethyl, trifluoromethyl, ...

[0041] According to the embodiments of this disclosure, L is selected from single bonds, NH, -C(O)C(R) L (R) L )-、-C(O)N(R L )-、-C(R L (R) L )-;

[0042] According to the implementation scheme of this disclosure, each R L They may be the same or different, and are independently selected from H, without substitution, or optionally by one, two, or more R. L1 The following groups are substituted: C 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, C 6-8 aryl, 5-10 membered heteroaryl, 3-8 membered heterocyclic; or, two R groups L The atoms connected to each other form C 3-6 cycloalkyl groups, 3-6 membered heterocyclic groups;

[0043] According to the implementation scheme of this disclosure, each R L1 They may be the same or different, and are independently selected from halogens (e.g., F), oxo (=O), and C.1-6 Alkyl (e.g., methyl), C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 1-6 Alkyl-C 3-6 cycloalkyl;

[0044] According to the implementation scheme of this disclosure, each R L Same or different, selected independently from C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3- 6-cycloalkyl, C 3-6 Cycloalkenyl, C 6-8 Aryl, Halogenated C 6-8 Aryl, 5-6 quinary heteroaryl, 9-10 quinary heteroaryl, C 1-6 Alkyl-5-6-membered heteroaryl, 3-6-membered heterocyclic, 3-6-membered heterocyclic-C 1-6 Alkyl, C 3-6 cycloalkyl-C 1-6 Alkyl, C 1-6 Alkyl-C 3-6 cycloalkyl-C 1-6 Alkyl; or, two Rs L The atoms bonded to them form cyclopropyl, cyclobutyl, oxacyclobutyl, cyclopentyl, and cyclohexyl groups;

[0045] According to the implementation scheme of this disclosure, each R L They may be the same or different, and are independently selected from methyl, trifluoromethyl, difluoromethyl, 3-fluorophenyl, 4-fluorophenyl, imidazolyl, triazolyl, pyrimidinyl, thiazolyl, phenyl, oxacyclobutyl, pyridinyl, indole, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, fluorophenyl, Or, two Rs L The atoms connected to each other form

[0046] According to the embodiments of this disclosure, L is selected from single bonds, NH, (For example ),

[0047] According to embodiments of this disclosure, G is selected from unsubstituted or optionally replaced by one, two or more R. g The following groups are substituted: C 3-6 Cycloalkyl, 5-6 membered heterocyclic, 9-10 membered heterocyclic, C 6-8 Aryl, 5-6 quinary heteroaryl, 9-10 quinary heteroaryl;

[0048] According to embodiments of this disclosure, G is selected from unsubstituted or optionally replaced by one, two or more R. g The following groups may be substituted: thiazolyl, 2-oxabicyclohexyl, phenyl, cyclopropyl, triazine, oxadiazole, oxazole, thiazolyl, triazolyl, pyrimidinyl,

[0049] According to the implementation scheme of this disclosure, G is selected from...

[0050] According to the implementation scheme of this disclosure, each R g Whether the two are the same or different, they are independently selected from H, oxo (=O), and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C 3-6 cycloalkyl, C 1-6 Alkyl-NH-, C 3-6 cycloalkyl-NH-, halogenated C 3-6 cycloalkyl-NH-, C 1-6 Alkyl-NHC(O)-, C 1-6 Alkyl-C(O)NH-;

[0051] According to the implementation scheme of this disclosure, each R g They may be the same or different, and are independently selected from H, oxo (=O), methyl, ethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, cyclopropyl,

[0052] According to the implementation scheme of this disclosure, G is selected from H,

[0053] According to embodiments of this disclosure, the compound represented by formula (I) is selected from the following compounds:

[0054] Among them, A, X, Y, E1, E2, L, and G independently have the definitions described above.

[0055] According to embodiments of this disclosure, the compound represented by formula (I) is selected from the following compounds:

[0056] Among them, A, X, Y, E1, E2, L, and G independently have the definitions described above.

[0057] According to embodiments of this disclosure, the compound represented by formula (I) is selected from the following compounds:

[0058] Among them, E1, E2, L, G, R g R L They each possess the definitions described above independently.

[0059] According to embodiments of this disclosure, the compound represented by formula (I) is selected from the following compounds:

[0060] Among them, E2, R g R L They each possess the definitions described above independently.

[0061] According to embodiments of this disclosure, the compound represented by formula (I) is selected from the following compounds:

[0062] Among them, E2, R g R L They each possess the definitions described above independently.

[0063] According to embodiments of this disclosure, the compound represented by formula (I) is selected from the following compounds:

[0064] The present invention also provides a pharmaceutical composition comprising at least one of the compounds of formula (I) or a pharmaceutically acceptable salt thereof.

[0065] According to embodiments of this disclosure, the pharmaceutical composition further includes one or more pharmaceutically acceptable excipients.

[0066] This disclosure also provides the use of compounds of formula (I) or pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment and / or prevention of cardiovascular diseases:

[0067] According to the embodiments of this disclosure, the cardiovascular disease is selected from hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome, and coronary artery disease.

[0068] According to the embodiments of this disclosure, the cardiovascular disease is familial hypercholesterolemia.

[0069] According to the embodiments of this disclosure, the cardiovascular disease is autosomal dominant hypercholesterolemia.

[0070] This disclosure also provides a method for treating cardiovascular disease, comprising administering to a patient a therapeutically effective amount of at least one of the compounds of formula (I) or a pharmaceutically acceptable salt thereof.

[0071] According to embodiments of this disclosure, the method further includes the combined administration of one or more additional therapeutic agents.

[0072] According to embodiments of this disclosure, the therapeutic agent may be selected from alizumab, evokulumab, beroxizumab, RG7652, LY3015014, mAb316P, berberine, quercetin, ezetimibe, prilol, BMS-962476, atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

[0073] According to embodiments of this disclosure, the therapeutic agent may be selected from HMG-CoA reductase inhibitors, HMG-CoA synthase inhibitors, HMG-CoA reductase gene expression inhibitors, HMG-CoA synthase gene expression inhibitors, MTP / Apo B secretion inhibitors, CETP inhibitors, bile acid absorption inhibitors, cholesterol absorption inhibitors, cholesterol synthesis inhibitors, squalene synthase inhibitors, squalene epoxide inhibitors, squalene cyclase inhibitors, combinations of squalene epoxide / squalene cyclase inhibitors, fibrates, niacin, combinations of niacin and lovastatin, ion exchange resins, antioxidants, ACAT inhibitors, bile acid chelators, and PCSK9 translation inhibitors. Beneficial effects

[0074] This disclosure provides a compound of formula (I) which has good PCSK9 inhibitory activity and drug-like properties, and can be used as a PCSK9 inhibitor to lower blood lipids.

[0075] Terminology Definitions and Explanations

[0076] Unless otherwise stated, the definitions of groups and terms recorded in this application specification and claims, including definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples, can be arbitrarily combined and combined with each other. Such combinations and combinations of group definitions and compound structures should be understood as being within the scope of this application specification and / or claims.

[0077] Unless otherwise stated, the numerical ranges described in this specification and claims are equivalent to describing at least each specific integer value therein. For example, the numerical range "1-10" is equivalent to describing each integer value in the numerical range "1-10", namely 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0078] It should be understood that in this article, when describing one, two or more, "more" should refer to integers greater than 2, such as 3 or greater than or equal to 3, such as 3, 4, 5, 6, 7, 8, 9 or 10.

[0079] The context of this disclosure is used Represents a chemical bond.

[0080] Term "C" 1-10 "alkyl" refers to a straight-chain or branched saturated hydrocarbon group, preferably a straight-chain or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The alkyl group includes C... 1-3 Alkyl, C 1-6 Alkyl, C 3-6 Alkyl, C 1-10 Alkyl groups, etc. "C" 1-10 "Alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. 1-8 "Alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. 1-6 "Alkyl" means a straight-chain or branched alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, or their isomers.

[0081] Term "C" 3-10"Cycloalkyl" refers to a saturated monovalent or polyvalent monocyclic, bicyclic (e.g., fused ring, bridged ring, spiro ring) hydrocarbon ring or tricyclic alkane, preferably having 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The cycloalkyl group includes C... 3-8 cycloalkyl, C 3-5 cycloalkyl, C 6-8 cycloalkyl, C 3-4 cycloalkyl, C 5-6 Cycloalkyl, C6 cycloalkyl, C 3-10 Cycloalkyl groups, etc. The C... 3-10 Cycloalkyl groups can be monocyclic hydrocarbon groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl; or bicyclic hydrocarbon groups, such as borneolyl, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 2,7-diazaspiro[3,5]nonyl, 2,6-diazaspiro[3,4]octyl; or tricyclic hydrocarbon groups, such as adamantyl.

[0082] Term "C" 3-10 "Cycloalkenyl" refers to a monovalent or polyvalent monocyclic, bicyclic (e.g., fused ring, bridged ring, spiro ring) hydrocarbon ring, or tricyclic olefin containing one or more double bonds, preferably having 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The cycloalkenyl group includes C... 3-8 Cycloalkenyl, C 3-6 Cycloalkenyl. The C... 3-10 Cycloalkenyl groups can be monocyclic hydrocarbon groups, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, or cyclodecenyl, or bicyclic hydrocarbon groups and tricyclic hydrocarbon groups.

[0083] The term "3-10 membered heterocyclic group" refers to a monocyclic, bicyclic, or tricyclic saturated or unsaturated non-aromatic ring or ring system (preferably 3-8 membered heterocyclic group) containing 1-5 heteroatoms independently selected from N, O, and S, with monovalent or polyvalent rings of 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms. For example, a 3-8 membered heterocyclic group can be a monocyclic, bicyclic, or tricyclic saturated or unsaturated non-aromatic ring or ring system containing 3, 4, 5, 6, 7, or 8 ring atoms, wherein the 3-8 membered heterocyclic group contains 1-5 heteroatoms independently selected from N, O, and S. The bicyclic and tricyclic aromatic ring systems can be fused rings, spirocyclic rings, or bridged rings. The 3-10 membered heterocyclic group includes 3-8 membered heterocyclic groups and 5-6 membered heterocyclic groups. The 3-10 membered heterocyclic group can be connected to the rest of the molecule via any one of the carbon atoms or a nitrogen atom (if present). The 3-10 membered heterocyclic groups may include fused or bridged rings and spirocyclic rings. Specifically, the heterocyclic groups may include, but are not limited to: 3-membered rings, such as azirropropyl or oxacyclopropyl; 4-membered rings, such as azirrobutyl or oxacyclobutyl; 5-membered rings, such as tetrahydrofuranyl, dioxacyclopentenyl, pyrrolyl, imidazoalkyl, pyrazolyl, or pyrrololinyl; or 6-membered rings, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazinyl, or trithiaalkyl; or 7-membered rings, such as diazacycloheptyl. Optionally, the heterocyclic group may be benzofused. The heterocyclic group may be bicyclic, for example, but not limited to, 5,5-membered rings, such as hexahydrocyclopenta[c]pyrrolo-2(1H)-yl rings, or 5,6-membered bicyclic rings, such as hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl rings. The heterocyclic group can be partially unsaturated, meaning it can contain one or more double bonds, such as, but not limited to, dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrroleyl, 4H-[1,3,4]thiadiazinyl, 1,2,3,5-tetrahydrooxazolyl, or 4H-[1,4]thiazinyl. Alternatively, it can be benzofused, such as, but not limited to, dihydroisoquinolinyl. When the 3-10 membered heterocyclic group is linked to other groups to form the compounds of this disclosure, the carbon atom on the 3-10 membered heterocyclic group can be linked to other groups, or a heterocyclic atom (such as a nitrogen atom) on the ring of the 3-10 membered heterocyclic group can be linked to other groups. For example, when the 3-10 membered heterocyclic group is selected from piperazineyl or tetrahydropyrroleyl, the nitrogen atom or carbon atom on the piperazineyl group can be linked to other groups. Alternatively, when the 3-10 membered heterocyclic group is selected from piperidinyl, it can be the nitrogen atom on the piperidinyl ring or the carbon atom at the ortho, meta or para position connected to other groups.

[0084] Term "C" 6-10"Aryl" should preferably be understood to refer to a monocyclic, bicyclic (such as fused ring, bridged ring, spirocyclic) or tricyclic hydrocarbon ring having monovalent or polyvalent aromaticity or partial aromaticity with 6 to 10 carbon atoms. It can be a monoaromatic ring or a polyaromatic ring fused together. The term "C" 6-10 "Aryl" should be understood to preferably represent a monocyclic, bicyclic, or tricyclic hydrocarbon ring having 6, 7, 8, 9, or 10 carbon atoms, exhibiting monovalent or polyvalent aromaticity or partial aromaticity ("C"). 6-10 Aryl), particularly a ring with 6 carbon atoms (“C6 aryl”), such as phenyl; or biphenyl, or a ring with 9 carbon atoms (“C9 aryl”), such as indenyl or indenyl, or a ring with 10 carbon atoms (“C9 aryl”). 10 Aryl), such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl. When the C... 6-10 When the aryl group is substituted, it can be monosubstituted or polysubstituted. Furthermore, there are no restrictions on the substitution site; for example, it can be ortho, para, or meta substituted.

[0085] The term "5-10-membered heteroaryl" refers to a monocyclic, bicyclic, or tricyclic aromatic ring system having 5, 6, 7, 8, 9, or 10 ring atoms, wherein the ring atoms comprise 1-5 heteroatoms independently selected from N, O, and S, and the bicyclic and tricyclic aromatic ring systems can be fused rings, spirocyclic, or bridged rings (preferably 5-9-membered heteroaryl). The 5-9-membered heteroaryl contains 1-5 heteroatoms, preferably 1-3. Additionally, in each case, the 5-10-membered heteroaryl can be benzofused. The 5-10-membered heteroaryl includes 5-8-membered heteroaryl, 5-9-membered heteroaryl, 5-10-membered heteroaryl, 5-6-membered heteroaryl, 8-10-membered heteroaryl, 6-membered heteroaryl, etc. Examples of heteroaryl groups include, but are not limited to: 5-membered rings, such as oxazolyl, pyrazolyl, thiophene, thiazolyl, triazole, imidazolyl, etc.; 6-membered rings, such as pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, etc. The heterocyclic group may be bicyclic, including but not limited to: 5,5-membered rings, such as tetrahydrocyclopentanopyrazole; 5,6-membered rings, such as tetrahydroindole, tetrahydropyrazolopyridine, tetrahydroimidazopyridine, tetrahydrobenzisoxazole, tetrahydrobenzoxazole, tetrahydrobenzothiazole, tetrahydrobenzisoxazole, dihydrofuranopyrazole, tetrahydrobenzofuran, dihydrobenzofuran, tetrahydrobenzothiophene; 6,6-membered rings, such as tetrahydroquinoline; 5,7-membered rings, such as tetrahydrocycloheptazothiazole, tetrahydrocycloheptazofuran. The heterocyclic group can be tricyclic, including but not limited to: 6,7-dihydrospiro[cyclopropane-1,5-pyrrolo[1,2-c]imidazole]. When the 5-10 membered heteroaryl group is substituted, it can be monosubstituted or polysubstituted. Furthermore, there are no restrictions on the substitution site; for example, the hydrogen atom bonded to the carbon atom on the heteroaryl ring can be substituted, or the hydrogen atom bonded to the heteroatom on the heteroaryl ring can be substituted.

[0086] The term "spirocycle" refers to a ring system in which two rings share a single ring atom.

[0087] The term "fused ring" refers to a ring system in which two rings share two cyclic atoms.

[0088] The term "bridged ring" refers to a ring system in which two rings share three or more cyclic atoms.

[0089] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0090] "Halogenation" refers to the substitution of a substance by one or more halogens.

[0091] Unless otherwise stated, the definitions of terms in this document also apply to groups that contain the term; for example, the definition of alkyl also applies to the definition of alkyl-containing groups such as alkoxy (i.e., alkyloxy).

[0092] Unless otherwise stated, the term "compound" in the context of this disclosure shall be understood to include the compound itself and its tautomers, stereoisomers, solvates or isotopic labels.

[0093] Crystallization often produces solvates of the compounds disclosed herein. As used herein, a solvate is a combination of one or more molecules of the compounds disclosed and one or more solvent molecules.

[0094] The solvent can be water, in which case the solvate is a hydrate; alternatively, it can be an organic solvate.

[0095] As used herein, the term “acceptable” in relation to formulations, compositions or ingredients means that it does not have a lasting harmful effect on the overall health of the subject of treatment.

[0096] As used herein, the term "pharmaceutically acceptable" means a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds disclosed herein and is relatively non-toxic, i.e., that the substance can be administered to an individual without causing an adverse biological response or interacting adversely with any component contained in the composition.

[0097] Those skilled in the art will understand that the compounds of this disclosure can exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form base addition salts; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they can also form inner salts.

[0098] The term "tautomer" refers to a functional group isomer resulting from the rapid movement of an atom between two positions within a molecule. The compounds disclosed herein can exhibit tautomerism. Tautomers can exist in two or more interconvertible forms. Proton-transfer tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms. Tautomers generally exist in equilibrium form, and attempts to isolate a single tautomer typically yield a mixture whose physicochemical properties are consistent with those of the mixture of compounds. The equilibrium position depends on the intramolecular chemical characteristics. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form is dominant; while in phenols, the enol form is dominant. This disclosure encompasses all tautomeric forms of the compounds.

[0099] Based on their molecular structure, the compounds disclosed herein can be chiral, and therefore may exist in various enantiomeric forms. Consequently, these compounds can exist in racemic or optically active forms. The compounds disclosed herein cover isomers of each chiral carbon with an R or S configuration, or mixtures thereof, or racemates. The compounds disclosed herein, or intermediates thereof, can be isolated as enantiomers by chemical or physical methods known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are obtained from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as tartaric acid in R and S forms, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-benzenesulfonylproline), or various optically active camphorsulfonic acids. Chromatographic enantiomeric separation can also be advantageously performed using optically active resolving agents (e.g., dinitrobenzoylphenylglycine immobilized on silica gel, cellulose triacetate or other carbohydrate derivatives, or chiral derivatized isobutylene ester polymers). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, such as hexane / isopropanol / acetonitrile.

[0100] In this application, "pharmaceutical composition" refers to a formulation of the disclosed compound and a medium conventionally accepted in the art for delivering a bioactive compound to a mammal (e.g., a human). This medium includes pharmaceutically acceptable carriers. The purpose of the pharmaceutical composition is to facilitate administration to the organism, thereby promoting the absorption of the active ingredient and the exertion of its bioactivity.

[0101] In this application, "pharmaceuticalally acceptable excipients" include, but are not limited to, any adjuvants, carriers, excipients, flow aids, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that are permitted by the relevant government regulatory authorities to be acceptable for human or livestock use.

[0102] In this application, the term "prodrug" refers to a compound of this disclosure that can be converted into a biologically active form under physiological conditions or by solvation. The prodrugs of this disclosure are prepared by modifying functional groups in the compound; such modification can be performed conventionally or removed in vivo to obtain the parent compound. Prodrugs comprise compounds formed by attaching a hydroxyl or amino group to any group in the compound of this disclosure. When a prodrug of the compound of this disclosure is administered to a mammalian individual, the prodrug is cleaved to form a free hydroxyl group and a free amino group.

[0103] "Isotope" refers to all isotopes of atoms appearing in the compounds disclosed herein. Isotopes include those atoms having the same atomic number but different mass numbers. Examples of isotopes suitable for inclusion in the compounds disclosed herein are hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, respectively, for example, but not limited to, [examples of isotopes]. 2 H, 3 H, 13 C 14 C 15 N、 18 O、 31 P, 32 P, 35 S, 18 F and 36 C1. The isotopically labeled compounds of this disclosure can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the appended examples, using appropriate isotopically labeled reagents instead of non-isotopically labeled preparations. Such compounds have a variety of potential uses, for example, as standards and reagents in the determination of biological activity. In the case of stable isotopes, such compounds have the potential to advantageously alter biological, pharmacological, or pharmacokinetic properties.

[0104] The term "treatment" and other similar synonyms used in this article include the following meanings:

[0105] (i) To prevent the occurrence of disease or condition in mammals, especially when such mammals are susceptible to the disease or condition but have not yet been diagnosed with it;

[0106] (ii) To suppress a disease or symptom, that is, to curb its development;

[0107] (iii) To alleviate a disease or symptom, that is, to cause the condition of the disease or symptom to subside; or

[0108] (iv) To alleviate the symptoms caused by the disease or condition.

[0109] The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, with humans being the most preferred.

[0110] The term “therapeutic effective amount” refers to the amount of an active compound or drug that researchers, veterinarians, physicians, or other clinicians are searching for in tissues, systems, animals, individuals, or humans to elicit a biological or medical response. It includes one or more of the following: (1) prevention of disease: e.g., prevention of disease, disorder, or condition in individuals susceptible to disease, disorder, or symptom but not yet experiencing or exhibiting the pathology or symptoms of the disease; (2) suppression of disease: e.g., suppression of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., prevention of further development of the pathology and / or symptoms); (3) relief of disease: e.g., relief of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., reversal of the pathology and / or symptoms). Detailed Implementation

[0111] The technical solutions of this disclosure will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of this disclosure and should not be construed as limiting the scope of protection of this disclosure. All technologies implemented based on the above content of this disclosure are covered within the scope of protection intended by this disclosure.

[0112] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0113] Example 1

[0114] LiOH (76 mg, 3.0 mmol) was added to a stirred solution of methyl 6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-6-oxo-[1,3'-bipyridine]-3-carboxylic acid (300 mg, 0.6 mmol) in methanol (5 mL) and tetrahydrofuran (5 mL). The resulting mixture was stirred in air at room temperature for 4 hours. The mixture was concentrated under reduced pressure. The crude product (300 mg) was purified by pre-high performance liquid chromatography to give a grayish-white solid 6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-6-oxo-[1,3'-bipyridine]-3-carboxylic acid (3.4 mg, 99.6% purity).

[0115] LCMS(ESI,m / z):[M+H] + =459.15

[0116] 1H NMR (400MHz, DMSO-d6) δ12.93 (s, 1H), 8.70 (s, 1H), 8.29 (d, J = 2.6Hz, 1H), 8.2 5(s,2H),8.15(d,J=2.4Hz,1H),7.88(dd,J=9.6,2.6Hz,1H),7.81(d,J=9.2Hz ,1H),7.54(s,1H),7.05(t,J=73.9Hz,2H),6.54(d,J=9.6Hz,1H),4.33(s,2H) ,2.30–2.19(m,1H),2.19–2.09(m,1H),2.08–1.91(m,2H),1.68–1.52(m,2H).

[0117] Example 2

[0118] 1. Synthesis of compound a

[0119] At room temperature and in air, pyridine (309 mg, 3.9 mmol) and copper acetate (533 mg, 2.9 mmol) were added to a stirred solution of methyl 2-oxo-1H-pyridine-4-carboxylate (300 mg, 1.9 mmol) and 6-bromopyridine-3-boronic acid (395 mg, 1.9 mmol) in dichloromethane (5 mL). The resulting mixture was stirred at room temperature and in air for 1 day. The mixture was filtered, and the filter cake was washed with dichloromethane. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (1:1) to give methyl 6'-bromo-2-oxo-[1,3'-bipyridine]-4-carboxylate (100 mg) as a pale yellow solid. LCMS (ESI, m / z): [M+H]+ = 309.25.

[0120] 2. Synthesis of compound b

[0121] At room temperature, cuprous iodide (3 mg, 0.01 mmol) and potassium carbonate (71 mg, 0.5 mmol) and N-(2,6-dimethylphenyl)-6-hydroxypyridine-2-carboxamide (2.5 mg, 0.01 mmol) were added to a stirred solution of methyl 6'-bromo-2-oxo-[1,3'-bipyridine]-4-carboxylate (80 mg, 0.3 mmol) and dimethyl sulfoxide (1 mL) in air. The resulting mixture was stirred overnight at 100 °C under nitrogen atmosphere. The mixture was filtered, and the filter cake was washed with ethyl acetate. The mixture was then washed with brine. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridine]-4-carboxylate (40 mg). LCMS (ESI, m / z): [M+H]+=473.20.

[0122] 3. Synthesis of Compound 0-1

[0123] In a solution of methyl 6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridine]-4-carboxylic acid (40 mg, 0.1 mmol) and methanol (0.5 mL) in THF (0.5 mL), water (0.5 mL) and lithium hydroxide monohydrate (7.1 mg, 0.2 mmol) were added. The resulting mixture was stirred at room temperature under nitrogen for 2 hours. The mixture was then concentrated under reduced pressure. The crude product (40 mg) was purified by pre-high performance liquid chromatography to give 6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-2-oxo-[1,3'-bipyridine]-4-carboxylic acid (2.6 mg).

[0124] LCMS(ESI,m / z):[M+H] + =459.20

[0125] 1H NMR (400MHz, DMSO-d6) δ8.32–8.14(m,2H),7.96(d,J=2.7Hz,1H),7.70(d,J=7.0Hz,1H),7.51–7.38(m,2H),7.2 4–6.83(m,3H),6.64–6.49(m,2H),4.39–4.27(m,2H),2.22–2.05(m,2H),1.99–1.85(m,2H),1.59–1.46(m,2H).

[0126] Example 3

[0127] 1. Synthesis of compound a

[0128] N-[(1S,3R)-3-hydroxycyclopentyl]tert-butyl carbamate (5.0 g, 24.8 mmol), dichloromethane (100 mL), triethylamine (7.5 g, 74.5 mmol), DMAP (0.6 g, 5.0 mmol), and p-toluenesulfonyl chloride (9.4 g, 49.6 mmol) were added sequentially to a single-necked flask, and the reaction was carried out overnight at room temperature. Dichloromethane (100 mL) was added, and the mixture was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, and the crude product was purified by reverse-phase reaction to give a yellow solid N-[(1S,3R)-3-[(4-methylbenzenesulfonyl)oxy]cyclopentyl]tert-butyl carbamate (2.3 g, 26.0% yield). LCMS (ESI, m / z): [M+H] + =356.1.

[0129] 2. Synthesis of compound b

[0130] 2-Chloro-5-(difluoromethoxy)pyrimidine (200 mg, 1.1 mmol), N,N-dimethylformamide (50 mL), and sodium hydrosulfide (310.5 mg, 5.5 mmol) were added sequentially to a single-necked flask, and the mixture was reacted at 110 °C for 1 hour under nitrogen protection. Potassium carbonate (765.5 mg, 5.5 mmol) and N-[(1S,3R)-3-[(4-methylbenzenesulfonyl)oxy]cyclopentyl]carbamate tert-butyl ester (393.7 mg, 1.1 mmol) were added to the above solution, and the reaction was continued overnight at 110 °C. After cooling to room temperature, the mixture was diluted with water (100 mL) and extracted with ethyl acetate. The organic phases were combined, dried with anhydrous sodium sulfate, and the organic phase was condensed to obtain the crude product. The crude product was then purified by reverse phase to give a yellow solid N-[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]thioalkyl}cyclopentyl]tert-butyl carbamate (200 mg, 44.9% yield), LCMS (ESI, m / z): [M+H] + =362.1.

[0131] 3. Synthesis of compound c

[0132] To a single-necked flask, N-[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]thioalkyl}cyclopentyl]tert-butyl carbamate (200 mg, 0.5 mmol) and a 1,4-hexacyclic solution of hydrochloric acid (4.0 M) (10 mL) were added sequentially, and the reaction was carried out at room temperature for 1 hour. The solvent was condensed to obtain a yellow crude product (1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]thioalkyl}cyclopentane-1-amine (200 mg). LCMS (ESI, m / z): [M+H] + =262.1.

[0133] 4. Synthesis of Compound 1

[0134] To a single-necked flask, 6'-chloro-[1,3'-bipyridine]-2-one (80 mg, 0.4 mmol), pyrrolidone (5 mL), potassium tert-butoxide (173.7 mg, 1.5 mmol), (1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]thioalkyl}cyclopentane-1-amine (101.1 mg, 0.4 mmol), and t-Buxphos Pd G3 (61.5 mg, 0.1 mmol) were added sequentially. The mixture was reacted at 110 °C for 5 hours under nitrogen protection. After cooling to room temperature, ethyl acetate (100 mL) was added, and the mixture was washed with water. The organic phase was dried with anhydrous sodium sulfate, filtered, and the solvent was condensed to obtain the crude product, which was then purified by high performance liquid chromatography to obtain 6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]thioalkyl}cyclopentyl]amino}-[1,3'-bipyridine]-2-one (3.2 mg).

[0135] LCMS(ESI,m / z):[M+H] + =432.1

[0136] 1 H NMR(400MHz,MeOD-d4)δ8.52(s,2H),7.97(d,J=2.6Hz,1H),7.67–7.56(m,2H),7.48-7.45(m,1H),7.11-6.75(m,1H),6.69–6.60(m,2H),6.50 -6.47(m,1H),4.60(s,1H),4.44-4.38(m,1H),4.27-4.20(m,1H),2.55 –2.41(m,1H),2.39–2.22(m,2H),2.17-2.10(m,1H),1.82–1.63(m,2H).

[0137] Example 4

[0138] 1. Synthesis of compound a

[0139] Under nitrogen atmosphere, a mixture of 2(1H)-pyridone (1.0 g, 10.5 mmol), 2-chloro-5-iodopyridine (2.6 g, 11.0 mmol), copper iodide (0.8 g, 4.2 mmol), 1,2-bis(methylamino)ethane (0.7 g, 8.4 mmol), and potassium carbonate (4.3 g, 31.5 mmol) in 1,4-dioxane (10 mL) was stirred at 130 °C for 3 hours. The mixture was cooled to room temperature. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (5:1) to give 6'-chloro-[1,3'-bipyridine]-2-one (740 mg, yield 34.0%) as a white solid. LCMS (ESI, m / z): [M+H] + =207.15.

[0140] 2. Synthesis of compound b

[0141] A solution of 6′-chloro-[1,3′-bipyridine]-2-1 (350 mg, 1.7 mmol) and sodium hydrosulfide (284 mg, 5.1 mmol) in N,N-dimethylformamide (30 mL) was stirred at 120 °C in air for 3 hours. The resulting mixture was used directly in the next step without further purification. LCMS (ESI, m / z): [M+H] + =205.15.

[0142] 3. Synthesis of compound c

[0143] Potassium carbonate (609 mg, 4.4 mmol) was added in portions to a stirred solution of 6′-sulfanilamide-[1,3′-bipyridine]-2-1 (300 mg, 1.4 mmol) and N-[(1S,3R)-3-[(4-methylbenzenesulfonyl)oxy]cyclopentyl]carbamate (522 mg, 1.4 mmol) in N,N-dimethylformamide (30 mL). The mixture was cooled to room temperature. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure after filtration. The residue was purified by reversed-phase chromatography to give N-[(1S,3S)-3-{[1,3'-bipyridine]-2-ylsulfanilamide cyclopentyl]carbamate tert-butyl (350 mg, yield 61.5%). LCMS (ESI, m / z): [M+H] + =388.25.

[0144] 4. Synthesis of compound d

[0145] A solution of tert-butyl N-[(1S,3S)-3-{[1,3'-bipyridine]-2-ylsulfamethoxycyclopentyl]carbamate (320 mg, 0.8 mmol) in DCM (5 mL, 1.5 mmol) in 1,4-dioxane (4.0 M) was stirred at 0 °C in air for 1 hour. The mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS (ESI, m / z): [M+H] + =288.00.

[0146] 5. Synthesis of Compound 2

[0147] 2-Chloro-5-(difluoromethoxy)pyrimidine (94 mg, 0.5 mmol) was aliquoted into a 5 mL solution of 6′-{[(1S,3S)-3-aminocyclopentyl]sulfanilamide}-[1,3′-bipyridine]-2-1 (150 mg, 0.5 mmol) and N,N-diisopropylethylamine (0.3 mL, 1.5 mmol) in dimethyl sulfoxide. The resulting mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The mixture was purified by reversed-phase chromatography to give 13.5 mg of 6′-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]sulfanilamide}-[1,3′-bipyridine]-2-1.

[0148] LCMS(ESI,m / z): [M+H] + =432.10

[0149] 1 H NMR (400MHz, MeOD-d4) δ8.46(d,J=2.5Hz,1H),8.19(s,2H),7.80–7.55(m,3H),7.42(d,J=8.6Hz,1H),6.94–6.59(m,2H),6.57–6.47(m,1H), 4.44(t,J=6.6Hz,1H),4.30(t,J=7.0Hz,1H),2.57–2.41(m,1H),2.29–2.16(m,2H),2.15–2.11(m,1H),1.79–1.62(m,2H),1.51–1.28(m,1H)

[0150] Example 5

[0151] 1. Synthesis of compound a

[0152] At room temperature and in air, 1,2-bis(methylamino)ethane (146 mg, 1.6 mmol) and potassium carbonate (862 mg, 6.2 mmol) were added to a 1,4-dioxane (5 mL) solution containing 3-chloro-6-iodopyridine (500 mg, 2.0 mmol), 2(1H)-pyridone (207 mg, 2.1 mmol), and copper iodide (158 mg, 0.8 mmol). The resulting mixture was stirred at 100 °C for 2 hours under nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography to give 1-(6-chloropyrazin-3-yl)pyridine-2-1 (90 mg, yield 20.84%). LCMS (ESI, m / z): [M+H] + =207.90.

[0153] 2. Synthesis of Compound 3

[0154] At room temperature and in air, a solution of (1S,3S)-n1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclopentane-1,3-diamine (80 mg, 0.3 mmol) and 1-(6-chloropyridin-3-yl)pyrimidin-2-1 (68 mg, 0.3 mmol) in 1,4-dioxane (2 mL) was mixed with methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (26 mg, 0.03 mmol) and potassium tert-butoxide (147 mg, 1.2 mmol). The resulting mixture was stirred at 110 °C for 2 hours under nitrogen. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography to obtain 1-(6-{(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)pyridine-2-1 (13.5 mg).

[0155] LCMS(ESI,m / z):[M+H] + =416.10

[0156] 1H NMR(400MHz, CDCl3-d)δ8.19(s,2H),7.91(dd,J=7.0,2.1Hz,1H),7.79(d,J=9.5Hz,1H),7.46-7.28(m,1H),6.75(d,J=9.5Hz,1H),6.68–6.58(m,1H ),6.46–6.20(m,2H),5.36(d,J=7.1Hz,1H),5.14(d,J=6.6Hz,1H),4.48- 4.42(m,2H),2.49–2.28(m,2H),2.11(t,J=6.8Hz,2H),1.68–1.59(m,2H).

[0157] Example 6

[0158] 1. Synthesis of compound a

[0159] At room temperature and in air, 1,2-bis(methylamino)ethane (1.2 g, 8.4 mmol) and potassium carbonate (4.36 g, 31.5 mmol) were added to a 1,4-dioxane (10 mL) solution containing 5-chloro-2-iodopyridine (2.64 g, 11.0 mmol), 2(1H)-pyridone (1.0 g, 10.5 mmol), and copper iodide (0.8 g, 4.2 mmol). The resulting mixture was stirred at 130 °C for 2 hours under nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1) to give 5′-chloro-[1,2′-bipyridine]-2-1 (670 mg, purity 30.84%). LCMS(ESI,m / z):[M+H] + =207.15

[0160] 2. Synthesis of Compound 4

[0161] At room temperature and in air, a solution of (1S,3S)-n1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclopentane-1,3-diamine (350 mg, 1.4 mmol) and 5'-chloro-[1,2'-bipyridine]-2-one (296 mg, 1.4 mmol) in 1,4-dioxane (5 mL) was mixed with methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (113 mg, 0.1 mmol) and potassium tert-butoxide (643 mg, 5.7 mmol). The resulting mixture was stirred at 110 °C for 2 hours under nitrogen. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography to obtain 5'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-[1,2'-bipyridine]-2-1 (16.5 mg, purity 95.0%).

[0162] LCMS(ESI,m / z):[M+H] + =415.10

[0163] 1 H NMR (400MHz, DMSO-d6) δ8.23(d,J=10.4Hz,2H),7.87(d,J=2.9Hz,1H),7.75(dd,J=7.0,2.1Hz,1H),7.58–7.44(m,2H),7.39(d,J=8.7Hz,1H),7.27–6 .78(m,2H),6.45–6.43(m,1H),6.38–6.16(m,2H),4.33–4.30(m,1H),3.95 (q,J=6.2Hz,1H),2.28–2.07(m,2H),2.01–1.80(m,2H),1.62–1.44(m,2H).

[0164] Example 7

[0165] 1. Synthesis of compound a

[0166] At 0 °C and in air, 1,1-bis(acetoxy)-3-oxo-3h-1l^[5],2-benzoiodo-1-acetic acid ester (2.7 g, 6.4 mmol) was added to a stirred solution of N-(3-hydroxy-2,3-dihydro-1h-indole-1-acyl)carbamate tert-butyl (800 mg, 3.2 mmol) in dichloromethane (10 mL). The resulting mixture was stirred overnight at room temperature in air. The resulting mixture was filtered, the filter cake was washed with dichloromethane, and the filtrate was concentrated under reduced pressure. It was purified by silica gel column chromatography, eluted with PE / EA (5:1) to give a white solid N-(3-oxo-1,2-dihydroindole-1-acyl)carbamate tert-butyl ester (600 mg, yield 75.61%).

[0167] 2. Synthesis of compound b

[0168] Sodium acetate (530 mg, 6.4 mmol) and hydroxylamine hydrochloride (337 mg, 4.8 mmol) were added to a methanol (200 mL) and water (2 mL) solution of N-(3-oxo-1,2-dihydroindene-1-yl)carbamate tert-butyl ester (800 mg, 3.2 mmol) at room temperature and air. The resulting mixture was stirred overnight at 80 °C. The mixture was then cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to give N-[(3Z)-3-(hydroxyimino)-1,2-dihydroindene-1-yl]carbamate tert-butyl ester (800 mg). LCMS (ESI, m / z): [M+H] + =263.15.

[0169] 3. Synthesis of compound c

[0170] Ammonia-methanol solution (20 mL) was added to a methanol (200 mL) solution of tert-butyl N-[(3Z)-3-(hydroxyimino)-1,2-dihydroindole-1-yl)carbamate (1.0 g, 3.8 mmol) and Raney nickel (1.1 g, 19.0 mmol). The resulting mixture was stirred for 2 h at room temperature under a hydrogen atmosphere. The mixture was filtered, the filter cake was washed with methanol, and the mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography to give tert-butyl N-(3-amino-2,3-dihydro-1h-indole-1-yl)carbamate (930 mg, yield 98.24%) as a yellow oil. LCMS (ESI, m / z): [M+H] + =249.10.

[0171] 4. Synthesis of compound d

[0172] To a solution of N-(3-amino-2,3-dihydro-1h-indole-1-yl)carbamate (930 mg, 3.7 mmol) and N,N-diisopropylethylamine (968 mg, 7.4 mmol) in dimethyl sulfoxide (10 mL), 2-chloro-5-(difluoromethoxy)pyrimidine (1.0 g, 5.6 mmol) was added. The resulting mixture was stirred at 120 °C in air for 2 h. The mixture was then cooled to room temperature. The resulting mixture was extracted with ethyl acetate, and the combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography to give N-(3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}-2,3-dihydro-1h-indole-1-yl)carbamate tert-butyl ester (900 mg, yield 61.24%) as a yellow oil. LCMS(ESI,m / z): [M+H] + =393.20.

[0173] 5. Synthesis of compound e

[0174] Hydrochloric acid was added to a solution of N-(3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}-2,3-dihydro-1h-indole-1-yl)carbamate (300 mg, 0.7 mmol) in 1,4-dioxane (3 mL) (4.0 M) (3 mL) at room temperature and air. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The mixture was concentrated under reduced pressure to give a grayish-white solid N1-[5-(difluoromethoxy)pyrimidin-2-yl]-2,3-dihydro-1h-indene-1,3-diamine (290 mg). LCMS (ESI, m / z): [M+H] + =293.20.

[0175] 6. Synthesis of compound 13-A

[0176] At room temperature and in an air atmosphere, a solution of N-methylpyrrolidone (2 mL) containing N1-[5-(difluoromethoxy)pyrimidin-2-yl]-2,3-dihydro-1h-indene-1,3-diamine (200 mg, 0.6 mmol) and 6'-chloro-[1,3'-bipyridine]-2-1 (141 mg, 0.6 mmol) was mixed with 54 mg (0.068 mmol) of methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) and 307 mg (2.7 mmol) potassium tert-butoxide. The resulting mixture was stirred at 110 °C for 5 h under nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was extracted with ethyl acetate, the combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The 6'-{[(1R,3R)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}-2,3-dihydro-1h-indene-1-yl]amino}-[1,3'-bipyridine]-2-1 (12.4 mg) was purified by pre-high performance liquid chromatography.

[0177] LCMS(ESI,m / z):[M+H] + =463.20

[0178] 1 H NMR (400MHz, DMSO-d6) δ8.30 (s, 2H), 8.00 (t, J = 2.0Hz, 1H), 7.79 (dd, J = 8.6, 3.3 Hz,1H),7.63(dd,J=6.8,2.1Hz,1H),7.55–7.45(m,1H),7.47–7.36(m,2H),7.36– 7.23(m,4H),6.97(dd,J=73.9,3.0Hz,1H),6.60(d,J=8.9Hz,1H),6.47(dt,J=9. 2,0.9Hz,1H),6.30(td,J=6.7,1.4Hz,1H),5.80–5.50(m,2H),2.43–2.27(m,2H).

[0179] Example 8

[0180] Synthesis of Compound 13-B

[0181] At room temperature and in an air atmosphere, a solution of N-methylpyrrolidone (2 mL) containing N1-[5-(difluoromethoxy)pyrimidin-2-yl]-2,3-dihydro-1h-indene-1,3-diamine (200 mg, 0.6 mmol) and 6'-chloro-[1,3'-bipyridine]-2-1 (141 mg, 0.6 mmol) was mixed with 54 mg (0.068 mmol) of methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) and 307 mg (2.7 mmol) potassium tert-butoxide. The resulting mixture was stirred at 110 °C for 5 h under nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was extracted with ethyl acetate, the combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The 6'-{[(1R,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}-2,3-dihydro-1h-indole-1-yl]amino}-[1,3'-bipyridine]-2-1 (14.8 mg) was purified by pre-high performance liquid chromatography.

[0182] LCMS(ESI,m / z):[M+H] + =463.20

[0183] 1 H NMR (400MHz, DMSO-d6) δ8.32 (s, 2H), 8.00 (d, J = 2.7Hz, 1H), 7.86 (d, J = 8.4Hz, 1H),7.65(dd,J=6.8,2.1,0.7Hz,1H),7.55–7.42(m,2H),7.35–7.23(m,5H),7 .00(d,J=73.9Hz,1H),6.72–6.66(m,1H),6.47(dd,J=9.1,1.1Hz,1H),6.30(d d,J=6.7,1.4Hz,1H),5.45–5.43(m,2H),2.97–2.94(m,1H),1.86-1.83(m,1H).

[0184] Example 9

[0185] 1. Synthesis of compound a

[0186] Add 1-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)cyclopropane-1-carboxylic acid (200 mg, 0.5 mmol) and dichloromethane (3 mL) sequentially to a single-necked flask. Add thionyl chloride (586.8 mg, 5.0 mmol) dropwise at room temperature and react for 2 hours at room temperature. Reduce the solvent to dryness and dissolve in dichloromethane (2 mL). Add this solution dropwise to a dichloromethane (3 mL) solution containing 3-pyrroline (136.3 mg, 2.0 mmol) and triethylamine (499.2 mg, 5.0 mmol) at room temperature, and react for another 3 hours at room temperature. The solvent was condensed and purified by reverse phase to give (1S,3S)-N1-[5-(difluoromethoxy)pyrimidin-2-yl]-N3-{5-[1-(2,5-dihydropyrrole-1-carbonyl)cyclopropyl]pyridin-2-yl}cyclopentane-1,3-diamine (150 mg, 66.6% yield), LCMS (ESI, m / z): [M+H] + =457.2.

[0187] 2. Synthesis of Compound 14

[0188] (1S,3S)-N1-[5-(difluoromethoxy)pyrimidin-2-yl]-N3-{5-[1-(2,5-dihydropyrrole-1-carbonyl)cyclopropyl]pyridin-2-yl}cyclopentane-1,3-diamine (50 mg, 0.1 mmol), dichloromethane (3 mL), chloroform (3 mL), and manganese dioxide (95.2 mg, 1.1 mmol) were added sequentially to a single-necked flask, and the mixture was reacted overnight at 40 °C. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with methanol. The filtrate was condensed to dryness and purified by high-performance liquid chromatography to give (1S,3S)-N1-[5-(difluoromethoxy)pyrimidin-2-yl]-N3-{5-[1-(pyrrole-1-carbonyl)cyclopropyl]pyridin-2-yl}cyclopentane-1,3-diamine (12.4 mg).

[0189] LCMS(ESI,m / z):[M+H] + =455.2

[0190] 1H NMR (400MHz, DMSO-d6) δ8.22(s,2H),7.95(d,J=2.5Hz,1H),7.45-7.43(m,1H),7.35–7.28(m,3H),7.21-6.84(m,1H),6.63(d,J=6.8Hz,1 H),6.43–6.36(m,1H),6.24–6.18(m,2H),4.29-4.19(m,2H),2.13–2.02(m,2H),1.91–1.74(m,2H),1.56–1.38(m,4H),1.30–1.25(m,2H).

[0191] Example 10

[0192] 1. Synthesis of compound a

[0193] 1-(6-aminopyridin-3-yl)cyclopropane-1-carboxylic acid (300 mg, 1.6 mmol), N,N-dimethylformamide (6 mL), potassium carbonate (698.0 mg, 5.0 mmol), and methyl iodide (716.9 mg, 5.0 mmol) were added sequentially to a single-necked flask, and the reaction was carried out at room temperature for 3 hours. After the reaction, ethyl acetate (50 mL) was added, and the mixture was extracted with water. The organic phase was dried over anhydrous sodium sulfate and condensed to obtain crude 1-(6-aminopyridin-3-yl)cyclopropane-1-carboxylic acid ester (300 mg, crude product), which was a yellow oil. LCMS (ESI, m / z): [M+H] + =212.0.

[0194] 2. Synthesis of Compound 14-2

[0195] 1-(6-chloropyridin-3-yl)cyclopropane-1-carboxylic acid ester (100 mg, 0.5 mmol), pyrrolidone (5 mL), (1S,3S)-N1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclopentane-1,3-diamine (115.4 mg, 0.5 mmol), potassium tert-butoxide (212.0 mg, 1.9 mmol), and t-Buxphos Pd G3 (37.5 mg, 0.04 mmol) were added sequentially to a single-necked flask, and the mixture was reacted at 110 °C for 5 hours. After cooling to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, condensed, and purified by high-performance liquid chromatography to obtain 1-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)cyclopropane-1-carboxylic acid (10.1 mg).

[0196] LCMS(ESI,m / z): [M+H] + =406.2

[0197] 1 H NMR(400MHz,MeOD-d4)δ8.18(s,2H),7.84(d,J=2.3Hz,1H),7.53-7.50(m,1H),6.89-6.52(m,2H),4.42-4.36(m,1H) ,4.29-4.22(m,1H),2.31-2.24(m,2H),2.08-1.94(m,2H),1.66-1.57(m,2H),1.53-1.51(m,2H),1.08-1.06(m,2H).

[0198] Example 11

[0199] 1. Synthesis of compound a

[0200] 1-Benzylimidazol-4-carboxylic acid (500 mg, 2.4 mmol), N,N-dimethylformamide (5 mL), 6-bromopyridin-3-amine (427.8 mg, 2.4 mmol), HOBT (1002.3 mg, 7.4 mmol), and EDCI (575.8 mg, 3.7 mmol) were added sequentially to a single-necked flask, and the reaction was carried out overnight at room temperature. Ethyl acetate (50 mL) was added, and the mixture was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, and the crude product was purified by reverse-phase chromatography to give a yellow solid, 1-benzyl-N-(6-bromopyridin-3-yl)imidazol-4-carboxamide (300 mg, 33.9% yield). LCMS (ESI, m / z): [M+H] + =357.0.

[0201] 2. Synthesis of compound b

[0202] 1-Benzyl-N-(6-bromopyridin-3-yl)imidazol-4-carboxamide (300 mg, 0.8 mmol), N-methylpyrrolidone (10 mL), and potassium tert-butoxide (282.7 mg, 2.5 mmol) were added sequentially to a single-necked flask. Iodomethane (357.6 mg, 2.5 mmol) was added dropwise at 0 °C, and the reaction was carried out at 0 °C for 3 hours. The mixture was diluted with ethyl acetate (50 mL) and extracted with water. The combined organic phases were dried over anhydrous sodium sulfate, and the organic phase was condensed to obtain the crude product. The crude product was then purified by reverse phase to give 1-benzyl-N-(6-bromopyridin-3-yl)-N-methylimidazol-4-carboxamide (150 mg, 48.1% yield). LCMS (ESI, m / z): [M+H] + =371.0.

[0203] 3. Synthesis of compound c

[0204] 1-Benzyl-N-(6-bromopyridin-3-yl)-N-methylimidazolium-4-carboxamide (150 mg, 0.4 mmol), N-methylpyrrolidone (5 mL), (1S,3S)-N1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclopentane-1,3-diamine (98.6 mg, 0.4 mmol), potassium tert-butoxide (181.3 mg, 1.6 mmol), and t-Buxphos Pd G3 (32.1 mg, 0.04 mmol) were added sequentially to a single-necked flask, and the reaction was carried out at 110 °C for 5 hours under nitrogen protection. Cool to room temperature, add ethyl acetate (50 mL), wash with water, dry the organic phase with anhydrous sodium sulfate, condense to dryness, and then purify by reverse phase to give 1-benzyl-N-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-N-methylimidazolium-4-carboxamide (50 mg), LCMS (ESI, m / z): [M+H] + =535.2.

[0205] 4. Synthesis of Compound 15

[0206] 1-Benzyl-N-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-N-methylimidazolium-4-carboxamide (50 mg, 0.09 mmol), tetrahydrofuran (5 mL), triethylsilane (200 mg, 1.7 mmol), and anhydrous palladium on carbon (10% 20 mg, 0.2 mmol) were added sequentially to a single-necked flask. The reaction was carried out overnight at room temperature under nitrogen protection. The mixture was filtered, the filter cake was washed with ethyl acetate, the solvent was dried, and the mixture was purified by high-performance liquid chromatography to give N-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-N-methyl-1H-imidazolium-4-carboxamide (3.4 mg).

[0207] LCMS(ESI,m / z):[M+H] + =445.2

[0208] 1H NMR (400MHz, DMSO-d6) δ12.68(s,1H),8.24(s,2H),7.89(s,1H),7.60(s,1H),7.47(d,J=7.2Hz,1H),7.40-7.31(m,1H),7.22-6.85 (m,2H),6.70-6.40(m,1H),5.63(s,1H),4.46–4.15(m,2H),3.24(s,3H),2.23–2.01(m,2H),1.95-1.80(m,2H),1.60-1.40(m,2H).

[0209] Example 12

[0210] 1. Synthesis of compound a

[0211] To a single-necked flask, 1H-imidazol-4-carboxylic acid (500 mg, 4.4 mmol), N,N-dimethylformamide (20 mL), 6-bromopyridin-3-amine (771.7 mg, 4.4 mmol), HOBT (1.8 g, 13.3 mmol), and EDCI (1.0 g, 6.6 mmol) were added sequentially, and the reaction was carried out overnight at room temperature. After the reaction, water (100 mL) was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and the crude product was purified by reverse-phase chromatography to give a yellow solid N-(6-bromopyridin-3-yl)-1H-imidazol-4-carboxamide (300 mg). LCMS (ESI, m / z): [M+H] + =267.0

[0212] 2. Synthesis of compound b

[0213] N-(6-bromopyridin-3-yl)-1H-imidazol-4-carboxamide (300 mg, 1.1 mmol), pyrrolidone (15 mL), potassium tert-butoxide (378.1 mg, 3.3 mmol), and methyl iodide (478.3 mg, 3.3 mmol) were added sequentially to a flask, and the reaction was carried out at room temperature for 2 hours. Ethyl acetate (100 mL) was added, and the mixture was washed with water. The organic phase was dried over anhydrous sodium sulfate, and after shrinkage, N-(6-bromopyridin-3-yl)-N,1-dimethylimidazol-4-carboxamide (500 mg) was obtained. LCMS (ESI, m / z): [M+H] + =295.0.

[0214] 3. Synthesis of Compound 15-1

[0215] N-(6-bromopyridin-3-yl)-N,1-dimethylimidazol-4-carboxamide (100 mg, 0.3 mmol), pyrrolidone (10 mL), (1S,3S)-N1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclopentane-1,3-diamine (82.7 mg, 0.3 mmol), potassium tert-butoxide (152.1 mg, 1.4 mmol), and t-Buxphos Pd G3 (53.8 mg, 0.07 mmol) were added sequentially to a single-necked flask, and the mixture was reacted at 110 °C for 5 hours. After cooling to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, condensed, and purified by high performance liquid chromatography to obtain N-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-N,1-dimethylimidazol-4-carboxamide (12.4 mg).

[0216] LCMS(ESI,m / z):[M+H] + =459.2

[0217] 1 H NMR(400MHz,DMSO-d6)δ8.23(s,2H),7.72(s,1H),7.48-7.42(m,2H),7.31–6.80(m,3H),6.61(d,J=6.9Hz,1H), 6.42(d,J=8.7Hz,1H),4.32-4.22(m,2H),3.58(s,3H),2.14-2.07(m,2H),1.94–1.79(m,2H),1.57–1.41(m,2H).

[0218] Example 13

[0219] 1. Synthesis of compound a

[0220] 1,3-Thiazol-4-carboxylic acid (500 mg, 3.8 mmol), N,N-dimethylformamide (10 mL), 6-bromopyridin-3-amine (669.9 mg, 3.8 mmol), HOBT (1569.6 mg, 11.6 mmol), and EDCI (901.6 mg, 5.8 mmol) were added sequentially to a single-necked flask, and the reaction was carried out overnight at room temperature. After the reaction, water (100 mL) was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and the crude product was purified by reverse-phase chromatography to give N-(6-bromopyridin-3-yl)-1,3-thiazol-4-carboxamide (500 mg). LCMS (ESI, m / z): [M+H] + =283.9

[0221] 2. Synthesis of compound b

[0222] N-(6-bromopyridin-3-yl)-1,3-thiazolyl-4-carboxamide (500 mg, 1.7 mmol), pyrrolidone (5 mL), potassium tert-butoxide (592.4 mg, 5.2 mmol), and methyl iodide (749.3 mg, 5.2 mmol) were added sequentially to a flask, and the mixture was reacted at 0 °C for 3 hours. Ethyl acetate (100 mL) was added, and the mixture was washed with water. The organic phase was dried over anhydrous sodium sulfate, condensed, and purified by reverse phase to give N-(6-bromopyridin-3-yl)-N-methyl-1,3-thiazolyl-4-carboxamide (450 mg). LCMS (ESI, m / z): [M+H] + =298.0.

[0223] 3. Synthesis of Compound 15-2

[0224] N-(6-bromopyridin-3-yl)-N-methyl-1,3-thiazolyl-4-carboxamide (80 mg, 0.2 mmol), dimethyl sulfoxide (5 mL), (1S,3S)-N1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclopentane-1,3-diamine (65.5 mg, 0.2 mmol), cuprous iodide (2.5 mg, 0.01 mmol), potassium carbonate (148.3 mg, 1.1 mmol), and N-(2,6-dimethylphenyl)-6-hydroxypyridin-2-carboxamide (6.5 mg, 0.03 mmol) were added sequentially to a single-necked flask, and the reaction was carried out at 110 °C for 5 hours under nitrogen protection. After cooling to room temperature, ethyl acetate (50 mL) was added, and the mixture was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, condensed, and purified by high performance liquid chromatography to obtain N-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-N-methyl-1,3-thiazolyl-4-carboxamide (12.1 mg).

[0225] LCMS(ESI,m / z):[M+H] + =462.1

[0226] 1H NMR (400MHz, DMSO-d6) δ8.88(s,1H),8.23(s,2H),7.96–7.75(m,1H),7.65(s,1H),7.44(d,J=7.2Hz,1H),7.24-6.85(m,2H),6.65(d, J=6.9Hz,1H),6.35(d,J=8.9Hz,1H),4.30-4.23(m,1H),4.22-4.15(m,1H),2.14–1.99(m,2H),1.90-1.70(m,2H),1.55-1.35(m,2H).

[0227] Example 14

[0228] 1. Synthesis of compound a

[0229] 1-Methyl-1,2,4-triazol-3-amine (1.0 g, 10.1 mmol), 1,4-dioxane (50 mL), 2-chloro-5-iodopyridine (2.7 g, 11.2 mmol), Xantphos (1.2 g, 2.0 mmol), and cesium carbonate (9.9 g, 30.6 mmol) were added sequentially to a single-necked flask. Pd₂(dba)₃ (0.9 g, 1.0 mmol) was added under nitrogen protection, and the reaction was carried out at 100 °C for 5 hours under nitrogen protection. The solvent was condensed to dryness, and water (100 mL) was added. The mixture was extracted with ethyl acetate. The organic phases were combined and condensed to dryness, and purified by reverse-phase chromatography to give a yellow solid, 6-chloro-N-(1-methyl-1,2,4-triazol-3-yl)pyridine-3-amine (1.1 g).

[0230] LCMS(ESI,m / z): [M+H] + =210.0

[0231] 2. Synthesis of compound b

[0232] 6-Chloro-N-(1-methyl-1,2,4-triazol-3-yl)pyridine-3-amine (400 mg, 1.9 mmol), pyrrolidone (5 mL), and potassium tert-butoxide (1.1 g, 9.5 mmol) were added sequentially to a flask. Acetic anhydride (584.3 mg, 5.7 mmol) was added dropwise under ice bath conditions, and the reaction was carried out at room temperature for 5 hours. Water (50 mL) was added, and the mixture was extracted with dichloromethane. The organic phases were combined and condensed to dryness, and purified by reverse-phase reaction to give a yellow solid N-(6-chloropyridine-3-yl)-N-(1-methyl-1,2,4-triazol-3-yl)acetamide (100 mg).

[0233] LCMS(ESI,m / z): [M+H] + =252.1

[0234] 3. Synthesis of Compound 16

[0235] N-(6-chloropyridin-3-yl)-N-(1-methyl-1,2,4-triazol-3-yl)acetamide (100 mg, 0.4 mmol), pyrrolidone (5 mL), (1S,3S)-N1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclopentane-1,3-diamine (106.7 mg, 0.4 mmol), and cesium carbonate (178.3 mg, 1.6 mmol) were added sequentially to a single-necked flask. t-Buxphos Pd G3 (63.1 mg, 0.1 mmol) was added under nitrogen protection, and the reaction was carried out at 100 °C for 5 hours under nitrogen protection. The solvent was reduced to dryness, water (100 mL) was added, and the mixture was extracted with ethyl acetate. The organic phases were combined and condensed, and the crude product was purified by high performance liquid chromatography to obtain N-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-N-(1-methyl-1,2,4-triazol-3-yl)acetamide (6.8 mg).

[0236] LCMS(ESI,m / z):[M+H] + =460.2

[0237] 1 H NMR(400MHz,MeOD-d4)δ8.36(s,1H),8.18(s,2H),7.97–7.92(m,1H),7.46–7.36(m,1H),6.90–6.52(m,2H),4.41-4 .35(m,1H),4.33-4.26(m,1H),3.93(s,3H),2.31–2.20(m,2H),2.13(s,3H),2.05–1.39(m,2H),1.66–1.52(m,2H).

[0238] Example 15

[0239] Synthesis of Compound 16-1

[0240] N-(6-chloropyridin-3-yl)-N-(1-methyl-1,2,4-triazol-3-yl)acetamide (100 mg, 0.4 mmol), pyrrolidone (5 mL), (1S,3S)-N1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclopentane-1,3-diamine (106.7 mg, 0.4 mmol), and cesium carbonate (178.3 mg, 1.6 mmol) were added sequentially to a single-necked flask. t-Buxphos Pd G3 (63.1 mg, 0.1 mmol) was added under nitrogen protection, and the reaction was carried out at 100 °C for 5 hours under nitrogen protection. The solvent was reduced to dryness, water (100 mL) was added, and the mixture was extracted with ethyl acetate. The organic phases were combined and condensed to dryness. The crude product was purified by high performance liquid chromatography to obtain a light yellow solid N2-[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]-N5-(1-methyl-1,2,4-triazol-3-yl)pyridine-2,5-diamine (10.2 mg).

[0241] LCMS(ESI,m / z):[M+H] + =418.2

[0242] 1 H NMR(400MHz,MeOD-d4)δ8.18(s,2H),8.15(d,J=2.7Hz,1H),8.02(s,1H),7.65-7.62(m,1H),6.89–6.52(m,2H) ,4.40-4.35(m,1H),4.27-4.22(m,1H),3.80(s,3H),2.34–2.19(m,2H),2.08–1.89(m,2H),1.67-1.52(m,2H).

[0243] Example 16

[0244] 1. Synthesis of compound a

[0245] 2-(6-chloropyridin-3-yl)acetic acid (500 mg, 2.6 mmol), N-methylpyrrolidone (5 mL), (1S,3S)-N1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclopentane-1,3-diamine (657.9 mg, 2.6 mmol), potassium tert-butoxide (1209.1 mg, 10.7 mmol), and t-Buxphos Pd G3 (213.9 mg, 0.2 mmol) were added sequentially to a single-necked flask, and the reaction was carried out at 110 °C for 5 hours under nitrogen protection. Water (30 mL) was added, and the mixture was extracted with ethyl acetate. The aqueous phase was condensed to dryness and purified by reverse phase to give (6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)acetic acid (500 mg). LCMS (ESI, m / z): [M+H] + =380.1.

[0246] 2. Synthesis of compound b

[0247] Add (200 mg, 0.5 mmol) of (6-{[(1S, 3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)acetic acid and 3 mL of dichloromethane to a single-necked flask. Add thionyl chloride (627.1 mg, 5.2 mmol) dropwise at room temperature and react for 2 hours at room temperature. Reduce the solvent to dryness and dissolve in dichloromethane (3 mL). Add this solution dropwise to a dichloromethane (3 mL) solution containing 3-pyrroline (109.3 mg, 1.5 mmol) and triethylamine (266.7 mg, 2.6 mmol) at room temperature and react for another 3 hours at room temperature. The solvent was condensed and purified by reverse phase to give 2-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-(2,5-dihydropyridin-1-yl)acetone (100 mg, 44.1% yield), LCMS (ESI, m / z): [M+H] + =431.2.

[0248] 3. Synthesis of Compound 17

[0249] 2-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-(2,5-dihydropyridin-1-yl)acetone (60 mg, 0.1 mmol), dichloromethane (1.5 mL), chloroform (1.5 mL), and manganese dioxide (181.76 mg, 2.1 mmol) were added sequentially to a single-necked flask, and the mixture was reacted overnight at 40 °C. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with methanol. The filtrate was condensed to dryness and purified by high-performance liquid chromatography to obtain 2-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-(pyrrolo-1-yl)acetone (12.4 mg).

[0250] LCMS(ESI,m / z):[M+H] + =429.2

[0251] 1 H NMR (400MHz, DMSO-d6) δ8.23(s,2H),7.90(d,J=2.4Hz,1H),7.55–7.50(m,2H),7.48–7.27(m,2H),7.84-7.61(m,1H),6.51(d,J=6.9Hz, 1H),6.43(d,J=8.6Hz,1H),6.35–6.30(m,2H),4.33-4.20(m,2H),4.12(s,2H),2.15-2.05(m,2H),1.92-1.79(m,2H),1.56–1.40(m,2H).

[0252] Example 17

[0253] Synthesis of Compound 17-1

[0254] HATU (125.3 mg, 0.3 mmol) and DIEA (85.2 mg, 0.7 mmol) were added to a stirred solution of (6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]aminocyclopentyl]aminopyridin-3-yl)acetic acid (50 mg, 0.1 mmol) and 3-pyrrolline (9.1 mg, 0.1 mmol) in dichloromethane (1 mL). The resulting mixture was stirred at room temperature for another 2 hours. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography to give 2-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-(2,5-dihydropyridin-1-yl)acetone (13 mg).

[0255] LCMS(ESI,m / z): [M+H] + =431.20

[0256] 1 H NMR (400MHz, DMSO-d6) δ8.23(s,2H),7.80(d,J=2.4Hz,1H),7.45(d,J=7.2Hz,1H),7.28–7.17(m,1H),7.22–6.85(m,1H),6.46–6.36( m,2H),5.91(s,2H),4.37–4.17(m,4H),4.06(t,J=4.0Hz,2H),3.43(s,2H),2.14–2.06(m,2H),1.94–1.81(m,2H),1.58–1.40(m,2H).

[0257] Example 18

[0258] 1. Synthesis of compound a

[0259] To a solution of 6'-chloro-[1,3'-bipyridine]-2-one (1.0 g, 4.8 mmol) and N-[(1S,3S)-3-aminocyclopentyl]carbamate tert-butyl ester (970 mg, 4.8 mmol) in toluene (100 mL), potassium tert-butoxide (651 mg, 5.8 mmol), palladium acetate (43 mg, 0.2 mmol), and [2'-(diphenylphosphono)-[1,1'-binaphthyl]-2-yl]diphenylphosphine (120 mg, 0.2 mmol) were added. All mixtures were stirred overnight at 100 °C under nitrogen. The resulting mixture was filtered, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (1:9) to give a pale yellow solid of tert-butyl ((1S,3S)-3-((2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate (700 mg). LCMS (ESI, m / z): [M+H] + =371.30.

[0260] 2. Synthesis of compound b

[0261] At room temperature and in air, tert-butyl N-[(1S,3S)-3-({2-oxo-[1,3'-bipyridin]-6'-yl}amino)cyclopentyl]carbamate (700 mg, 1.9 mmol) and a 1,4-dioxane solution of hydrochloric acid (4.0 M) (10 mL, 5.8 mmol) were stirred for 3 hours in 30 mL of dichloromethane. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS (ESI, m / z): [M+H] + =271.25.

[0262] 3. Synthesis of Compound 18

[0263] To a stirred solution of 6'-{[(1S,3S)-3-aminocyclopentyl]amino}-[1,3'-bipyridine]-2-one (100 mg, 0.4 mmol) and 1,3-thiazolium-2-carboxylic acid (47 mg, 0.4 mmol) in DMF (5 mL), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (168 mg, 0.4 mmol) and N,N-diisopropylethylamine (143 mg, 1.1 mmol) were added in portions. The resulting mixture was purified by reversed-phase flash chromatography to give N-[(1S,3S)-3-({2-oxo-[1,3'-bipyridine]-6'-yl}amino)cyclopentyl]-1,3-thiazolium-2-carboxamide (15.5 mg).

[0264] LCMS(ESI,m / z):[M+H] + =382.10

[0265] 1 H NMR(400MHz,MeOD-d4)δ7.97(t,J=2.9Hz,2H),7.85(d,J=3.1Hz,1H),7.68–7.54(m,2H),7.47(dd,J=9.0,2.7Hz,1H),6.65–6.62(m,2H) ,6.49–6.46(m,1H),4.87-4.53(m,1H),4.42–4.39(m,1H),2.32–2.28(m,2H),2.17–2.14(m,1H),2.06–1.98(m,1H),1.80–1.59(m,2H).

[0266] Example 19

[0267] Synthesis of Compound 19

[0268] To a stirred solution of 6'-{[(1S,3S)-3-aminocyclopentyl]amino}-[1,3'-bipyridine]-2-one (100 mg, 0.4 mmol) and 2-oxabicyclo[2.1.1]hexane-1-carboxylic acid (47 mg, 0.4 mmol) in DMF (5 mL), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (168 mg, 0.4 mmol) and N,N-diisopropylethylamine (143 mg, 1.1 mmol) were added in portions at room temperature and in air. The reaction was quenched with water at room temperature. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure after filtration. The residue was purified by reversed-phase flash chromatography to obtain N-[(1S,3S)-3-({2-oxo-[1,3'-bipyridine]-6'-yl}amino)cyclopentyl]-2-oxabicyclo[2.1.1]hexane-1-carboxamide (13.5 mg, yield 9.59%, purity 99.2%).

[0269] LCMS(ESI,m / z): [M+H] + =381.15

[0270] 1 H NMR (400MHz, MeOD-d4) δ7.96 (d, J=2.6Hz, 1H), 7.69–7.54 (m, 2H), 7.46 (dd, J=8.9, 2.7Hz, 1H), 6.63–6.49 (m, 2H), 6.49–6. 46(m,1H),4.49–4.25(m,2H),3.89(s,2H),2.97(t,J=3.3Hz,1H),2.34–2.12(m,4H),2.09–1.79(m,2H),1.72–1.50(m,4H).

[0271] Example 20

[0272] Synthesis of Compound 20

[0273] Triethylamine (75 mg, 0.7 mmol) was added in portions to a stirred solution of 6'-{[(1S,3S)-3-aminocyclopentyl]amino}-[1,3'-bipyridine]-2-one (100 mg, 0.4 mmol) and phenyl chloroformate (58 mg, 0.4 mmol) in DCM (2 mL) at 0 °C in air. The reaction was quenched with water at room temperature. The resulting mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography to give N-[(1S,3S)-3-({2-oxo-[1,3'-bipyridine]-6'-yl}amino)cyclopentyl]phenyl carbamate (12 mg, yield 8.31%).

[0274] LCMS(ESI,m / z): [M+H] + =381.15

[0275] 1 H NMR(400MHz,MeOD-d4)δ7.97(dd,J=2.7,0.7Hz,1H),7.71–7.56(m,2H),7.46(dd,J=9.0,2.7Hz,1H),7.42–7.33(m,2H),7.21(t,J=7.5Hz,1H),7.16 –7.05(m,2H),6.69–6.58(m,2H),6.50–6.46(m,1H),4.38–4.35(m,1H),4. 18-4.14(m,1H),2.37–2.14(m,2H),2.13–1.86(m,2H),1.78–1.49(m,2H).

[0276] Example 21

[0277] Synthesis of Compound 21

[0278] Triethylamine (75 mg, 0.7 mmol) was added in portions to a stirred solution of 6'-{[(1S,3S)-3-aminocyclopentyl]amino}-[1,3'-bipyridine]-2-one (100 mg, 0.4 mmol) and cyclopropyl chlorocarbamate (44 mg, 0.4 mmol) in dichloromethane (10 mL). The reaction was quenched with water at room temperature. The resulting mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product (150 mg) was purified by pre-high performance liquid chromatography to give cyclopropyl N-[(1S,3S)-3-({2-oxo-[1,3'-bipyridine]-6'-yl}amino)cyclopentyl]carbamate (11.9 mg).

[0279] LCMS(ESI,m / z): [M+H] + =381.15

[0280] 1 H NMR(400MHz,MeOD-d4)δ7.96(d,J=2.6Hz,1H),7.70–7.57(m,2H),7.45(dd,J=9.0,2.7Hz,1H),6.72–6.56(m,2H),6.48–6.46(m,1H),4.2 9(q,J=6.7Hz,1H),4.11(t,J=6.9Hz,1H),3.97–3.32(m,1H),2.34–2.07(m,2H),1.95–1.88(m,2H),1.56–1.53(m,2H),0.84–0.56(m,4H).

[0281] Example 22

[0282] 1. Synthesis of compound a

[0283] 2-Chloro-5-(difluoromethoxy)pyrimidine (500 mg, 2.7 mmol), dimethyl sulfoxide (8 mL), N-[(1r,3r)-3-aminocyclobutyl]carbamate tert-butyl ester (567.4 mg, 3.0 mmol), and N,N-diisopropylethylamine (715.8 mg, 5.5 mmol) were added sequentially to a single-necked flask, and the mixture was reacted at 110 °C for 5 hours. Water (100 mL) was added, and the mixture was extracted with ethyl acetate. The organic phases were combined and condensed to dryness, and purified by reversed-phase chromatography to give N-[(1R,3R)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclobutyl]carbamate tert-butyl ester (700 mg). LCMS (ESI, m / z): [M+H] + =331.2.

[0284] 2. Synthesis of compound b

[0285] N-[(1R,3R)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclobutyl]carbamate tert-butyl ester (700 mg, 2.1 mmol) and a 1,4-dioxane hydrochloric acid solution (4.0 M) (20 mL) were added sequentially to a flask, and the reaction was carried out at room temperature for 5 hours. The solvent was then condensed to dryness, yielding a yellow solid (1R,3r)-N1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclobutane-1,3-diamine hydrochloride (700 mg, crude product). LCMS (ESI, m / z): [M+H] + =231.2.

[0286] 3. Synthesis of Compound 25

[0287] Add (1R,3R)-N1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclobutane-1,3-diamine hydrochloride (100 mg, 0.4 mmol), pyrrolidone (5 mL), (6'-chloro-[1,3'-bipyridine]-2-one (89.7 mg, 0.4 mmol), and cesium carbonate (194.9 mg, 1.7 mmol) sequentially to a single-necked flask. Then, add t-Buxphos Pd under nitrogen protection. G3 (69.0 mg, 0.1 mmol) was reacted at 100 °C for 5 hours under nitrogen protection. The solvent was dried out, water (50 mL) was added, and the mixture was extracted with ethyl acetate. The organic phases were combined and dried out, and the crude product was purified by high performance liquid chromatography to give 6'-{[(1R,3R)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclobutyl]amino}-[1,3'-bipyridine]-2-one (11.0 mg).

[0288] LCMS(ESI,m / z):[M+H] + =401.1

[0289] 1 H NMR(400MHz,Methanol-d4)δ8.20(s,2H),7.98-7.95(m,1H),7.67–7.57(m,2H),7.51-7.48(m,1H) ),6.92–6.52(m,3H),6.50-6.46(m,1H),4.55–4.43(m,1H),4.42–4.33(m,1H),2.51-2.51(m,4H).

[0290] Example 23

[0291] 1. Synthesis of compound a

[0292] 2-Chloro-5-(difluoromethoxy)pyrimidine (500 mg, 2.7 mmol), dimethyl sulfoxide (8 mL), N-[(1S,3S)-3-aminocyclobutyl]carbamate tert-butyl ester (567.4 mg, 3.0 mmol), and N,N-diisopropylethylamine (715.8 mg, 5.5 mmol) were added sequentially to a single-necked flask, and the reaction was carried out at 110 °C for 5 hours. Water (100 mL) was added, and the mixture was extracted with ethyl acetate. The organic phases were combined and condensed to dryness, then purified by reverse-phase chromatography to give a yellow solid N-[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclobutyl]carbamate tert-butyl ester (701 mg). LCMS (ESI, m / z): [M+H] + =331.2.

[0293] 2. Synthesis of compound b

[0294] N-[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclobutyl]carbamate tert-butyl ester (701 mg, 2.1 mmol) and a 1,4-dioxane hydrochloric acid solution (4.0 M) (20 mL) were added sequentially to a flask, and the reaction was carried out at room temperature for 5 hours. The solvent was then condensed to dryness, yielding a yellow solid (1S,3S)-N1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclobutane-1,3-diamine hydrochloride (700 mg, crude product). LCMS (ESI, m / z): [M+H] + =231.2

[0295] 3. Synthesis of Compound 26

[0296] Add (1S,3S)-N1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclobutane-1,3-diamine hydrochloride (100 mg, 0.4 mmol), pyrrolidone (5 mL), (6'-chloro-[1,3'-bipyridine]-2-one (89.7 mg, 0.4 mmol), and cesium carbonate (194.9 mg, 1.7 mmol) sequentially to a single-necked flask. Then, add t-Buxphos Pd under nitrogen protection. G3 (69.0 mg, 0.1 mmol) was reacted at 100 °C for 5 hours under nitrogen protection. The solvent was dried out, water (50 mL) was added, and the mixture was extracted with ethyl acetate. The organic phases were combined and dried out, and the crude product was purified by high performance liquid chromatography to give 6'-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclobutyl]amino}-[1,3'-bipyridine]-2-one (12.0 mg).

[0297] LCMS(ESI,m / z):[M+H] + =401.1

[0298] 1 H NMR(400MHz,MeOD-d4)δ8.20(s,2H),8.00–7.95(m,1H),7.67–7.57(m,2H),7.51-7.48(m,1H), 6.92–6.52(m,3H),6.50-6.48(m,1H),4.22-4.03(m,2H),2.99-2.91(m,2H),1.96-1.95(m,2H).

[0299] Example 24

[0300] 1. Synthesis of compound a

[0301] At room temperature and in air, N,N-diisopropylethylamine (1.2 g, 9.9 mmol) was added to a stirred solution of N-[(1S,2S)-2-aminocyclopentyl]carbamate tert-butyl (1.0 g, 4.9 mmol) and 2-chloro-5-(difluoromethoxy)pyrimidine (1.3 g, 7.4 mmol) in dimethyl sulfoxide (10 mL). The resulting mixture was stirred at 120 °C for 2 hours in air. The mixture was cooled to room temperature. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure after filtration. The residue was purified by reversed-phase flash chromatography to give N-[(1S,2S)-2-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]carbamate tert-butyl (1.2 g, 69.79% yield). LCMS(ESI,m / z): [M+H] + =345.15

[0302] 2. Synthesis of compound b

[0303] At room temperature and in air, hydrochloric acid was added to a solution of 1,4-dioxane (4.0 M) (5 mL) of N-[(1S,2S)-2-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]carbamate tert-butyl (500 mg, 1.4 mmol) in 1,4-dioxane (5 mL). The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The mixture was concentrated under reduced pressure to give a yellow solid (1S,2S)-n1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclopentane-1,2-diamine (490 mg).

[0304] LCMS(ESI,m / z): [M+H] + =245.15

[0305] 3. Synthesis of Compound 29

[0306] At room temperature and in air, a solution of (1S,2S)-n1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclopentane-1,2-diamine (200 mg, 0.8 mmol) and 6′-chloro-[1,3′-bipyridine]-2-1 (169 mg, 0.8 mmol) in 1,4-dioxane (1 mL) was mixed with methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (65 mg, 0.08 mmol) and potassium tert-butoxide (367 mg, 3.2 mmol). The resulting mixture was stirred overnight at 110 °C under nitrogen. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product (70 mg) was purified by pre-high performance liquid chromatography to obtain 6'-{[(1S,2S)-2-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}-[1,3'-bipyridine]-2-1 (14.7 mg).

[0307] 1 H NMR (400MHz, DMSO-d6) δ8.23 (s, 2H), 7.91 (d, J = 2.7Hz, 1H), 7.58 (dd, J = 6.8, 2.0Hz,1H),7.54–7.45(m,2H),7.40(dd,J=8.9,2.7Hz,1H),7.23–6.80(m,2H ),6.61(d,J=8.9Hz,1H),6.44(d,J=9.2Hz,1H),6.27(td,J=6.7,1.3Hz,1H), 4.18–4.06(m,2H),2.16–2.07(m,2H),1.76–1.70(m,2H),1.54–1.47(m,2H).

[0308] Example 25

[0309] 1. Synthesis of compound a

[0310] Under a nitrogen atmosphere, 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (0.7 g, 1.2 mmol) and cesium carbonate (5.9 g, 18.3 mmol) were added to a solution of 1,4-dioxane (10 mL) containing 2-amino-4-nitrobenzonitrile (1.0 g, 6.1 mmol), 6′-chloro-[1,3′-bipyridine]-2-1 (1.2 g, 6.1 mmol), and tris(dibenzylene-BASE-acetone)dipalladium (0.5 g, 0.6 mmol). The resulting mixture was stirred at 110 °C for 2 hours under a nitrogen atmosphere. The mixture was then cooled to room temperature. The mixture was filtered, and the filter cake was collected and washed with methanol to obtain 4-nitro-2-({2-oxo-[1,3'-bipyridine]-6'-yl}amino)benzonitrile (1.2 g). LCMS (ESI, m / z): [M+H] + =334.10.

[0311] 2. Synthesis of compound b

[0312] Ammonium chloride (96 mg, 1.8 mmol) was added to a solution of 4-nitro-2-({2-oxo-[1,3'-bipyridin]-6'-yl}amino)benzonitrile (300 mg, 0.9 mmol) and iron powder (251 mg, 4.5 mmol) in ethanol (1 mL) and water (0.2 mL) at room temperature and in air. The resulting mixture was stirred overnight at 80 °C in air. The mixture was allowed to cool to room temperature. The resulting mixture was filtered, and the filter cake was collected and washed with methanol. The residue was dissolved in dichloromethane and methanol (10 mL). The resulting mixture was concentrated under reduced pressure to give 4-amino-2-({2-oxo-[1,3'-bipyridin]-6'-yl}amino)benzonitrile (200 mg) as a yellow-green solid. LCMS (ESI, m / z): [M+H] + =304.10

[0313] 3. Synthesis of compound 31-1

[0314] To a solution of 4-amino-2-({2-oxo-[1,3'-bipyridin]-6'-yl}amino)benzonitrile (300 mg, 0.9 mmol), 2-chloro-5-(difluoromethoxy)pyrimidine (178 mg, 0.9 mmol), and tris(dibenzylene-BASE-acetone)palladium (45 mg, 0.04 mmol) in 1,4-dioxane (3 mL), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (57 mg, 0.1 mmol) and cesium carbonate (644 mg, 1.9 mmol) were added to 1,4-dioxane (3 mL) at room temperature and under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 2 hours under nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was extracted with ethyl acetate. The bound organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The product was purified by reversed-phase flash chromatography to obtain 4-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}-2-({2-oxo-[1,3'-bipyridine]-6'-yl}amino)benzonitrile (11.2 mg, yield 2.53%).

[0315] LCMS(ESI,m / z): [M+H] + =448.15

[0316] 1 H NMR (400MHz, DMSO-d6) δ10.30(s,1H),9.25(s,1H),9.03(d,J=2.5Hz,1H),8.60(s,2H),8.27(d,J=8.9Hz,1H),8.1 7(d,J=2.2Hz,1H),7.83–7.77(m,1H),7.67–7.53(m,3H),7.42–7.00(m,2H),6.54–6.51(m,1H),6.39–6.37(m,1H).

[0317] Example 26

[0318] 1. Synthesis of compound a

[0319] 2-Chlorothieno[2,3-d]pyrimidine (500 mg, 2.9 mmol), dimethyl sulfoxide (5 mL), N-[(1S,3S)-3-aminocyclopentyl]carbamate tert-butyl ester (586.9 mg, 2.9 mmol), and DIEA (1136.3 mg, 8.7 mmol) were added sequentially to a single-necked flask, and the mixture was reacted at 120 °C for 2 hours. After the reaction, ethyl acetate (50 mL) was added, and the mixture was washed with water. The organic phase was dried over anhydrous sodium sulfate, and the crude product was purified by reverse-phase chromatography to give a yellow solid N-[(1S,3S)-3-{thieno[2,3-d]pyrimidine-2-ylamino}cyclopentyl]carbamate tert-butyl ester (600 mg). LCMS (ESI, m / z): [M+H] + =335.1.

[0320] 2. Synthesis of compound b

[0321] N-[(1S,3S)-3-{thieno[2,3-d]pyrimidin-2-ylamino}cyclopentyl]carbamate tert-butyl ester (500 mg, 1.5 mmol) and 1,4-dioxane hydrochloride (4.0 mmol, 20 mL) were added sequentially to a flask, and the mixture was reacted at room temperature for 2 hours. After drying, a yellow solid (1S,3S)-N1-{thieno[2,3-d]pyrimidin-2-yl}cyclopentane-1,3-diamine (500 mg) was obtained.

[0322] LCMS(ESI,m / z): [M+H] + =235.1

[0323] 3. Synthesis of Compound 37

[0324] (1S,3S)-N1-{thieno[2,3-d]pyrimidin-2-yl}cyclopentane-1,3-diamine (150 mg, 0.6 mmol), dimethyl sulfoxide (5 mL), N-(6-chloropyridin-3-yl)-N-(1-methyl-1,2,4-triazol-3-yl)acetamide (15.5 mg, 0.06 mmol), N-(2,6-dimethylphenyl)-6-hydroxypyridin-2-carboxamide (15.5 mg, 0.06 mmol), potassium carbonate (353.8 mg, 2.5 mmol), and cuprous iodide (6.1 mg, 0.03 mmol) were added sequentially to a single-necked flask, and the mixture was reacted at 110 °C for 5 hours. After cooling to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, condensed, and purified by high performance liquid chromatography to obtain N-(1-methyl-1,2,4-triazol-3-yl)-N-(6-{[(1S,3S)-3-{thieno[2,3-d]pyrimidin-2-ylamino}cyclopentyl]amino}pyridin-3-yl)acetamide (12.4 mg).

[0325] LCMS(ESI,m / z):[M+H] + =450.2

[0326] 1 H NMR (400MHz, DMSO-d6) δ8.78(s,1H),8.43(s,1H),7.85(s,1H),7.44(d,J=7.3Hz,1H),7.30–7.18(m,3H),6.79(d,J=7.0Hz,1H),6.46(d, J=8.9Hz,1H),4.43-4.38(m,1H),4.29-4.24(m,1H),3.83(s,3H),2.17-2.08(m,2H),2.02(s,3H),1.98-1.80(m,2H),1.59–1.43(m,2H).

[0327] Example 27

[0328] 1. Synthesis of compound a

[0329] 2-Chloroquinoline (300 mg, 1.8 mmol) and tert-butyl N-[(1S,3S)-3-aminocyclopentyl]carbamate (402 mg, 2.0 mmol) were stirred in DMSO (3 mL), and DIEA (706 mg, 5.4 mmol) was added dropwise at room temperature. The resulting mixture was stirred at 120 °C in air for 2 hours. Purification was performed by reversed-phase flash chromatography to give tert-butyl N-[(1S,3S)-3-(quinazoline-2-amino)cyclopentyl]carbamate (300 mg). LCMS (ESI, m / z): [M+H] + =329.25

[0330] 2. Synthesis of compound b

[0331] HCl was added dropwise to dioxane (1 mL) under air at room temperature, and then added to a stirred solution of N-[(1S,3S)-3-(quinazoline-2-amino)cyclopentyl]carbamate tert-butyl ester (200 mg, 0.6 mmol) and dioxane (2 mL). The resulting mixture was stirred under air at room temperature for 2 hours. The mixture was then concentrated under reduced pressure to give (1S,3S)-n1-(quinazoline-2-yl)cyclopentane-1,3-diamine (120 mg). LCMS (ESI, m / z): [M+H] + =229.10

[0332] 3. Synthesis of Compound 38

[0333] t-BuXPhos Pd G3 (17.4 mg, 0.1 mmol) and t-BuOK (98 mg, 0.8 mmol) were added separately to a mixture of (1S,3S)-n1-(quinazolin-2-acyl)cyclopentane-1,3-diamine (50 mg, 0.21 mmol) and N-(6-chloropyridin-3-acyl)-N-(1-methyl-1,2,4-triazol-3-acyl)acetamide (55 mg, 0.2 mmol) in NMP (1.5 mL) under a nitrogen atmosphere at room temperature. The mixture was added in portions. The resulting mixture was stirred at 110 °C for 2 hours under a nitrogen atmosphere. The crude product (50 mg) was purified by Prep-HPLC to obtain N-(1-methyl-1,2,4-triazol-3-yl)-N-(6-{(1S,3S)-3-(quinazolin-2-ylamino)cyclopentyl]aminopyridin-3-yl)acetamide (5.5 mg).

[0334] LCMS(ESI,m / z):[M+H] + =444.30

[0335] 1 H NMR(400MHz,DMSO-d6)δ9.09(s,1H),8.43(s,1H),7.90–7.82(m,1H),7.77(dd,J=8.1,1.5Hz ,1H),7.70–7.63(m,1H),7.52–7.41(m,2H),7.33–7.25(m,1H),7.24–7.17(m,1H),6.81(d,J =6.8Hz,1H),6.47(d,J=8.8Hz,1H),4.49(q,J=7.0Hz,1H),4.28(q,J=6.6Hz,1H),3.83(s,3H ),2.22–2.09(m,2H),2.02(s,3H),1.95–1.93(m,1H),1.93–1.82(m,1H),1.63–1.42(m,2H).

[0336] Example 28

[0337] 1. Synthesis of compound a

[0338] 2-Chloro-5h,6H,7h-cyclopenta[d]pyrimidine (300 mg, 1.9 mmol) and N-[(1S,3S)-3-aminocyclopentyl]carbamate tert-butyl ester (390 mg, 1.9 mmol) were stirred thoroughly in DMSO (3 mL), and DIEA (750 mg, 5.8 mmol) was added dropwise at room temperature. The resulting mixture was stirred at 120 °C in air for 3 days. Purification was performed by reversed-phase flash chromatography to obtain N-[(1S,3S)-3-{5H,6H,7h-cyclopenta[d]pyrimidine-2-amino}cyclopentyl]carbamate tert-butyl (300 mg). LCMS (ESI, m / z): [M+H] + =319.25

[0339] 2. Synthesis of compound b

[0340] HCl was added dropwise to dioxane (5 mL) at room temperature to a stirred solution of N-[(1S,3S)-3-{5H,6H,7h-cyclopenta[d]pyrimidin-2-amino}cyclopentyl]carbamate (500 mg, 1.5 mmol) and dioxane (10 mL). The resulting mixture was stirred at room temperature under air for 2 h. The mixture was then concentrated under reduced pressure. The result was (1S,3S)-n1-{5H,6H,7h-cyclopenta[d]pyrimidin-2-yl}cyclopentane-1,3-diamine (300 mg). LCMS (ESI, m / z): [M+H] + =219.10

[0341] 3. Synthesis of Compound 41

[0342] t-BuXPhos Pd G3 (54 mg, 0.1 mmol) and t-BuOK (308 mg, 2.7 mmol) were added, respectively, to a mixture of (1S,3S)-n1-{5H,6H,7H-cyclopenta[d]pyrimidine-2-yl}cyclopentane-1,3-diamine (150 mg, 0.6 mmol) and N-(6-chloropyridin-3-yl)-N-(1-methyl-1,2,4-triazol-3-yl)acetamide (170 mg, 0.6 mmol) in NMP (1.5 mL) at room temperature under a nitrogen atmosphere. The mixture was stirred in portions at 110 °C for 2 hours under a nitrogen atmosphere. The crude product (100 mg) was purified by Prep-HPLC to obtain N-(6-{(1S,3S)-3-{5H,6H,7h-cyclopenta[d]pyrimidin-2-ylaminocyclopentyl]aminopyridin-3-yl)-N-(1-methyl-1,2,4-triazol-3-yl)acetamide (3.5 mg).

[0343] LCMS(ESI,m / z):[M+H] +=434.20

[0344] 1 H NMR (400MHz, DMSO-d6) δ8.43 (s, 1H), 8.06 (s, 1H), 7.84 (d, J = 2.6Hz, 1H), 7.27 (dd, J=8.8,2.8Hz,1H),6.90(d,J=7.2Hz,1H),6.75(d,J=6.8Hz,1H),6.45(d,J=8.8Hz, 1H),4.37–4.29(m,1H),4.26–4.18(m,1H),3.83(s,3H),2.73–2.64(m,4H),2.17–2 .05(m,2H),2.02(s,3H),2.00-1.91(m,2H),1.91–1.72(m,2H),1.53–1.35(m,2H).

[0345] Example 29

[0346] 1. Synthesis of compound a

[0347] 3-Bromo-5-methyl-1,2,4-isodiazole (3.0 g, 18.4 mmol) and tert-butyl N-[(1S,3S)-3-aminocyclopentyl]carbamate (3.3 g, 16.7 mmol) were stirred thoroughly in MTBE (30 mL). Aphos Pd G3 (1.0 g, 1.6 mmol) and DBU (5.1 g, 33.4 mmol) were then added in portions under a nitrogen atmosphere at room temperature. The resulting mixture was stirred overnight at 60 °C under a nitrogen atmosphere. The mixture was concentrated under reduced pressure. Purification was performed by reversed-phase flash chromatography to give tert-butyl N-[(1S,3S)-3-[(5-methyl-1,2,4-oxadiazol-3-yl)amino]cyclopentylcarbamate (500 mg). LCMS (ESI, m / z): [M+H] + =282.20

[0348] 2. Synthesis of compound a

[0349] HCl was added dropwise to N-[(1S,3S)-3-[(5-methyl-1,2,4-oxadiazol-3-yl)amino]cyclopentylcarbamate (900 mg, 3.1 mmol) dioxane (18 mL) at room temperature under air. The resulting mixture was stirred at room temperature under air for 2 h. The mixture was then concentrated under reduced pressure. The result was (1S,3S)-n1-(5-methyl-1,2,4-oxadiazol-3-yl)cyclopentane-1,3-diamine (500 mg) as a white solid. LCMS (ESI, m / z): [M+H] +=183.20

[0350] 3. Synthesis of Compound 45-1

[0351] The mixture of (1S,3S)-n1-(5-methyl-1,2,4-oxadiazol-3-yl)cyclopentane-1,3-diamine (100 mg, 0.5 mmol) and N-(6-chloropyridin-3-yl)-N-(1-methyl-1,2,4-triazol-3-yl)acetamide (138.1 mg, 0.5 mmol) in dioxane (1 mL) was added to dioxane (1 mL) with (SP-4-1)-(1,3-bis[2,6-bis(1-ethylpropyl)phenyl]4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (230.5 mg, 0.2 mmol). Cs₂CO₃ (715.1 mg, 2.1 mmol) was added in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 90 °C under a nitrogen atmosphere. The crude product (100 mg) was purified by Prep-HPLC to give N-(6-{(1S,3S)-3-[(5-methyl-1,2,4-triazol-3-yl)amino]cyclopentyl]aminopyridin-3-yl)-N-(1-methyl-1,2,4-triazol-3-yl)acetamide (6.6 mg).

[0352] LCMS(ESI,m / z):[M+H] + =398.30

[0353] 1H NMR(400MHz, Acetonitrile-d3)δ8.08(s,1H),7.95(d,J=2.6Hz,1H),7.36(dd,J =8.8,2.7Hz,1H),6.46(d,J=8.8Hz,1H),5.39(d,J=7.0Hz,1H),5.16(d,J=6.8Hz ,1H),4.34–4.23(m,1H),4.03–3.93(m,1H),3.83(s,3H),2.38(s,3H),2.22–2.1 7(m,2H),2.08(s,3H),2.05–2.00(m,1H),1.93–1.84(m,1H),1.65–1.46(m,2H).

[0354] Example 30

[0355] 1. Synthesis of compound a

[0356] 2-Chloro-(300 mg, 1.9 mmol) and tert-butyl N-[(1S,3S)-3-aminocyclopentyl]carbamate (390 mg, 1.9 mmol) were stirred thoroughly in DMSO (3 mL), and DIEA (757 mg, 5.8 mmol) was added dropwise at room temperature. The resulting mixture was stirred at 120 °C in air for 2 hours. Purification was performed by reversed-phase flash chromatography under the following conditions: C18 silica gel column; mobile phase: water, ACN, gradient 0%–100% over 40 min; UV detector: 254 nm. Tert-butyl N-[(1S,3S)-3-(1,3-benzoxazole-2-amino)cyclopentyl]carbamate (300 mg) was obtained. LCMS (ESI, m / z): [M+H] + =318.25

[0357] 2. Synthesis of compound b

[0358] At room temperature, HCl was added dropwise to dioxane (1.5 mL), which was then added to a stirred solution of N-[(1S,3S)-3-(1,3-benzoxazole-2-amino)cyclopentyl]carbamate (300 mg, 0.9 mmol) dioxane (3 mL). The resulting mixture was stirred at room temperature under air for 2 hours. The mixture was then concentrated under reduced pressure to give (1S,3S)-n1-(1,3-benzoxazole-2-yl)cyclopentane-1,3-diamine (200 mg). LCMS (ESI, m / z): [M+H] + =218.10

[0359] 3. Synthesis of Compound 50

[0360] t-BuXPhos PdG3 (54 mg, 0.07 mmol) and t-BuOK (310 mg, 2.7 mmol) were added separately to a mixture of (1S,3S)-n1-(1,3-benzoxazole-2-acyl)cyclopentane-1,3-diamine (150 mg, 0.7 mmol) and N-(6-chloropyridin-3-acyl)-N-(1-methyl-1,2,4-triazol-3-acyl)acetamide (173 mg, 0.7 mmol) in NMP (2 mL) under stirring at room temperature and a nitrogen atmosphere. The resulting mixture was stirred at 110 °C for 2 hours under a nitrogen atmosphere. The resulting mixture was extracted with ethyl acetate. The bound organic layer was washed with brine and dried over anhydrous Na2SO4. The filtrate was concentrated under reduced pressure. The crude product (100 mg) was purified by Prep-HPLC to obtain N-(6-{(1S,3S)-3-(1,3-benzoxazol-2-ylamino)cyclopentyl]amino}pyridin-3-yl)-N-(1-methyl-1,2,4-triazol-3-yl)acetamide (12.0 mg).

[0361] LCMS(ESI,m / z):[M+H] + =433.20

[0362] 1 H NMR (400MHz, DMSO-d6) δ8.44(s,1H),7.99(d,J=7.0Hz,1H),7.86(d,J=2.6Hz,1H),7 .35–7.26(m,2H),7.24(d,J=7.7Hz,1H),7.10(t,J=7.6Hz,1H),7.00–6.93(m,1H),6 .90–6.79(m,1H),6.47(d,J=8.8Hz,1H),4.35–4.17(m,2H),3.83(s,3H),2.22–2.09 (m,2H),2.06–1.94(m,4H),1.93–1.83(m,1H),1.68–1.56(m,1H),1.55–1.42(m,1H).

[0363] Example 31

[0364] 1. Synthesis of compound a

[0365] Hydrochloric acid was added to a solution of tert-butyl N-(1,3-thiazol-4-acyl)carbamate (2.0 g, 9.9 mmol) in 1,4-dioxane (10 mL) at room temperature and air. The resulting mixture was stirred overnight at room temperature in air. The mixture was then concentrated under reduced pressure to give a white solid, 1,3-thiazol-4-amine (1.9 g).

[0366] 2. Synthesis of compound b

[0367] Acetyl chloride (1.1 g, 14.9 mmol) was added to a solution of 1,3-thiazol-4-amine (1.0 g, 9.9 mmol) and triethylamine (1.5 g, 14.9 mmol) in dichloromethane (10 mL) at 0 °C and in air. The resulting mixture was stirred overnight at room temperature in air. The filtrate was concentrated under reduced pressure. Purification by reversed-phase flash chromatography yielded N-(1,3-thiazol-4-yl)acetamide (450 mg, 31.69% yield). LCMS (ESI, m / z): [M+H] + =143.10

[0368] 3. Synthesis of compound c

[0369] To a solution of N-(1,3-thiazolyl-4-acyl)acetamide (420 mg, 2.9 mmol), 2-chloro-5-iodopyridine (742 mg, 3.1 mmol), and tris(dibenzylene-BASE-acetone)dipalladium (270 mg, 0.2 mmol) in 1,4-dioxane (5 mL), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (341 mg, 0.5 mmol) and cesium carbonate (2887 mg, 8.8 mmol) were added. The resulting mixture was stirred overnight at 110 °C under nitrogen. The mixture was cooled to room temperature. The mixture was filtered, and the filter cake was washed with ethyl acetate. The resulting mixture was extracted with ethyl acetate, and the combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. N-(6-chloropyridin-3-yl)-N-(1,3-thiazolyl-4-yl)acetamide (230 mg, yield 30.69%) was purified by reversed-phase flash chromatography. LCMS (ESI, m / z): [M+H] + =254.10

[0370] 4. Synthesis of Compound 53

[0371] Potassium tert-butoxide (367 mg, 3.2 mmol) was added to a stirred solution of (1S,3S)-n1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclopentane-1,3-diamine (200 mg, 0.8 mmol), N-(6-chloropyridin-3-yl)-N-(1,3-thiazolyl-4-yl)acetamide (218 mg, 0.8 mmol) and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (65 mg, 0.08 mmol) in N-methylpyrrolidone (2 mL) at room temperature and under a nitrogen atmosphere. The resulting mixture was stirred at 110 °C for 2 hours under nitrogen. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product (130 mg) was purified by pre-high performance liquid chromatography to give N-(6-{(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-N-(1,3-thiazolyl-4-yl)acetamide (12.8 mg).

[0372] LCMS(ESI,m / z):[M+H] + =462.15

[0373] 1H NMR(400MHz,DMSO-d6)δ9.82(s,1H),8.89(s,1H),8.24(s,2H),8.11(s,1H),7.48(d,J=7.3Hz,2H),7.26–6.7 9(m,2H),6.51(d,J=8.8Hz,1H),4.35–4.26(m,2H),2.16–2.07(m,2H),2.03–1.82(m,5H),1.61–1.42(m,2H).

[0374] Example 32

[0375]

[0376] 1. Synthesis of compound a

[0377] Acetyl chloride (2.1 g, 27.9 mmol) was added to a stirred solution of aniline (1.0 g, 10.7 mmol) and triethylamine (1.2 g, 11.8 mmol) in 10 mL of dichloromethane at 0 °C. The resulting mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure. The mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. Purification was performed by silica gel column chromatography, eluting with PE / EA (5:1), to give 1.3 g of white solid acetanilide. LCMS (ESI, m / z): [M+H] + =136.10

[0378] 2. Synthesis of compound b

[0379] A mixture of acetanilide (1.0 g, 7.3 mmol), cuprous iodide (0.2 g, 1.4 mmol), cesium carbonate (6.0 g, 18.4 mmol), and ethyl 2-oxocyclohexane-1-carboxylate (0.5 g, 3.3 mmol) in dimethyl sulfoxide (10 mL) was added to the mixture at room temperature and under nitrogen atmosphere. The mixture was stirred at 110 °C for 3 hours in air. The mixture was cooled to room temperature. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. Purification was performed by silica gel column chromatography, eluting with PE / EA (5:1) to give N-(6-chloropyridin-3-yl)-N-phenylacetamide (350 mg, 19.18%). LCMS (ESI, m / z): [M+H] + =247.10

[0380] 3. Synthesis of Compound 54

[0381] Under a nitrogen atmosphere at room temperature, potassium tert-butoxide (643 mg, 5.7 mmol) was added to a stirred solution of (1S,3S)-n1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclopentane-1,3-diamine (350 mg, 1.4 mmol), N-(6-chloropyridin-3-yl)-N-phenylacetamide (353 mg, 1.4 mmol), and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (113 mg, 0.1 mmol) in N-methylpyrrolidone (10 mL). The resulting mixture was stirred at 110 °C for 1 hour under nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by pre-high performance liquid chromatography to obtain N-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-N-phenylacetamide (12.3 mg).

[0382] LCMS(ESI,m / z):[M+H] + =455.20

[0383] 1 H NMR(400MHz, DMSO-d6)δ8.23(s,2H),8.00(d,J=3.6Hz,1H),7.67–6.69(m,9H),6.46(d,J=8.9Hz ,1H),4.33–4.24(m,2H),2.13–2.03(m,2H),1.92(s,3H),1.90–1.82(m,2H),1.56–1.54(m,2H).

[0384] Example 33

[0385] Synthesis of Compound 54-1

[0386] Under a nitrogen atmosphere at room temperature, potassium tert-butoxide (643 mg, 5.7 mmol) was added to a stirred solution of (1S,3S)-n1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclopentane-1,3-diamine (350 mg, 1.4 mmol), N-(6-chloropyridin-3-yl)-N-phenylacetamide (353 mg, 1.4 mmol), and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (113 mg, 0.1 mmol) in N-methylpyrrolidone (10 mL). The resulting mixture was stirred at 110 °C for 1 hour under nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The filtrate was purified by pre-high performance liquid chromatography to obtain N2-[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]-n5-phenylpyridine-2,5-diamine (19.2 mg).

[0387] LCMS(ESI,m / z):[M+H] + =413.15

[0388] 1 H NMR (400MHz, DMSO-d6) δ8.24 (s, 2H), 7.81 (d, J = 2.7Hz, 1H), 7.50 (s, 1H), 7.46 (d ,J=7.2Hz,1H),7.28–7.20(m,1H),7.14–6.84(m,3H),6.76–6.69(m,2H),6.64–6 .60(m,1H),6.49(d,J=8.8Hz,1H),6.39(d,J=6.8Hz,1H),4.32(p,J=7.0Hz,1H), 4.23(p,J=6.6Hz,1H),2.14–2.09(m,2H),1.96–1.79(m,2H),1.55–1.46(m,2H).

[0389] Example 34

[0390] 1. Synthesis of compound a

[0391] 2,2-Difluoroacetyl 2,2-difluoroacetate (710.2 mg, 4.1 mmol) and TEA (413.5 mg, 4.1 mmol) were added aliquots to a 48 mL solution of 6-chloro-n-phenylpyridin-3-amine (418.5 mg, 2.0 mmol) in DCM under a stirred atmosphere at 0 °C. The resulting mixture was stirred for 2 h at 0 °C in air. The mixture was then concentrated under reduced pressure to give N-(6-chloropyridin-3-yl)-2,2-difluoro-N-phenylacetamide (200 mg). LCMS (ESI, m / z): [M+H] + =283.15

[0392] 2. Synthesis of Compound 57-1

[0393] t-BuXPhos Pd G3 (84 mg, 0.1 mmol) and t-BuOK (476 mg, 4.2 mmol) were added to a mixture of N-(6-chloropyridin-3-acyl)-2,2-difluoro-N-phenylacetamide (300 mg, 1.0 mmol) and (1S,3S)-n1-[5-(difluoromethoxy)pyrimidin-2-acyl]cyclopentane-1,3-diamine (259 mg, 1.0 mmol) in NMP (3 mL). The resulting mixture was stirred at 110 °C for 2 hours under a nitrogen atmosphere. The crude product was purified by Prep-HPLC to give N-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-2,2-difluoro-N-phenylacetamide (1.5 mg).

[0394] LCMS(ESI,m / z):[M+H] + =491.25

[0395] 1 H NMR(400MHz, Acetonitrile-d3)δ8.20(s,3H),7.72–7.27(m,6H),6.81–6.41(m, 2H),6.32–5.90(m,3H),4.48–4.30(m,2H),2.35–2.19(m,4H),1.66–1.51(m,2H).

[0396] Example 35

[0397] 1. Synthesis of compound a

[0398] Sodium hydride (60 mg, 2.5 mmol) was slowly added to a stirred solution of 6-chloro-N-(1-methyl-1,2,4-triazol-3-yl)pyridin-3-amine (350 mg, 1.6 mmol) in N,N-dimethylformamide (4 mL) under a nitrogen atmosphere at 0 °C. The resulting mixture was stirred for another hour at room temperature. 3-fluorobenzoyl chloride (397 mg, 2.5 mmol) was slowly added dropwise to the mixture, and the resulting mixture was stirred overnight at room temperature. The reaction was quenched with ice water at room temperature. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. Purification was performed by silica gel column chromatography, eluting with PE / EA (1:2), to give N-(6-chloropyridin-3-yl)-3-fluoro-N-(1-methyl-1,2,4-triazol-3-yl)benzamide (160 mg). LCMS(ESI,m / z): [M+H] + =332.10

[0399] 2. Synthesis of Compound 59

[0400] Potassium tert-butoxide (137 mg, 1.2 mmol) was added to a stirred solution of (1S,3S)-n1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclopentane-1,3-diamine (150 mg, 0.6 mmol), N-(6-chloropyridin-3-yl)-3-fluoro-N-(1-methyl-1,2,4-triazol-3-yl)benzamide (203 mg, 0.6 mmol) and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (48 mg, 0.06 mmol) in 1,4-dioxane (2 mL) at room temperature and under a nitrogen atmosphere. The resulting mixture was stirred at 110 °C for 2 hours under nitrogen. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was purified by pre-high performance liquid chromatography to give N-(6-{(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-3-fluoro-N-(1-methyl-1,2,4-triazol-3-yl)benzamide (14.9 mg).

[0401] LCMS(ESI,m / z):[M+H] + =540.20

[0402] 1H NMR (400MHz, DMSO-d6) δ8.38(s,1H),8.23(s,2H),7.88(d,J=2.6Hz,1H),7.46(d,J=7.2Hz,1H),7.41–7.34(m,2H),7.29–7.22(m,3H),7.13(d ,J=74.0Hz,1H),6.85(s,1H),6.51(d,J=9.0Hz,1H),4.31–4.22(m,2H) ,3.75(s,3H),2.22–2.04(m,2H),1.91–1.83(m,2H),1.63–1.40(m,2H).

[0403] Example 36

[0404] 1. Synthesis of compound a

[0405] Sodium hydride (0.1 g, 7.1 mmol) was slowly added to a stirred solution of 6-chloro-N-(1-methyl-1,2,4-triazol-3-yl)pyridin-3-amine (1.0 g, 4.7 mmol) in 10 mL of N,N-dimethylformamide (0.1 g, 7.1 mmol). The resulting mixture was stirred at room temperature for another hour. 4-fluorobenzoyl chloride (1.1 g, 7.1 mmol) was slowly added dropwise to the mixture, and the resulting mixture was stirred at room temperature overnight. The reaction was quenched with ice water at room temperature. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. Purification was performed by silica gel column chromatography, eluting with PE / EA (1:2), to give a yellow solid N-(6-chloropyridin-3-yl)-4-fluoro-N-(1-methyl-1,2,4-triazol-3-yl)benzamide (930 mg). LCMS(ESI,m / z): [M+H] + =332.10

[0406] 2. Synthesis of Compound 60

[0407] Potassium tert-butoxide (91 mg, 0.8 mmol) was added to a stirred solution of (1S,3S)-n1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclopentane-1,3-diamine (100 mg, 0.4 mmol), N-(6-chloropyridin-3-yl)-3-fluoro-N-(1-methyl-1,2,4-triazol-3-yl)benzamide (135 mg, 0.4 mmol), and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (32 mg, 0.04 mmol) in 1,4-dioxane (2 mL) under nitrogen atmosphere at room temperature. The resulting mixture was stirred at 110 °C for 2 hours under nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was purified by pre-high performance liquid chromatography to give N-(6-{(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-4-fluoro-N-(1-methyl-1,2,4-triazol-3-yl)benzamide (7.8 mg, yield 3.53%).

[0408] LCMS(ESI,m / z):[M+H] + =540.25

[0409] 1 H NMR (400MHz, DMSO-d6) δ8.37(s,1H),8.23(s,2H),7.85(d,J=2.6Hz,1H),7.54–7.44(m,3H),7.35(s,1H),7.27–6. 78(m,4H),6.52(s,1H),4.31–4.22(m,2H),3.74(s,3H),2.13–2.10(m,2H),1.95–1.81(m,2H),1.55–1.50(m,2H).

[0410] Example 37

[0411] 1. Synthesis of compound a

[0412] To a mixture of 1,4-dioxane (10 mL) of 6-chloropyridin-3-amine (1.0 g, 7.7 mmol) and 3-bromopyridine (1.4 g, 9.3 mmol), cesium carbonate (7.6 g, 23.3 mmol), tris(dibenzylacetone)dipalladium (0.7 g, 0.7 mmol), and 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (0.45 g, 0.77 mmol) were added. The resulting mixture was stirred at 110 °C for 2 hours under nitrogen. The residue was purified by silica gel column chromatography, eluting with dichloromethane / methanol (10 / 1) to give 6-chloro-N-(pyridin-3-yl)pyridin-3-amine (800 mg). LCMS (ESI, m / z): [M+H] + =206.04

[0413] 2. Synthesis of compound b

[0414] A mixture of 6-chloro-N-(pyridin-3-yl)pyridin-3-amine (100 mg, 0.49 mmol) and cesium carbonate (47 mg, 1.4 mmol) was added to toluene (2 mL) and stirred in air at room temperature. The resulting mixture was stirred in air at 80 °C for 2 hours. The desired product was detected by LCMS. The residue was purified by silica gel column chromatography, eluting with dichloromethane / methanol (12 / 1) to give N-(6-chloropyridin-3-yl)-1-methyl-N-(pyridin-3-yl)imidazolium-4-carboxamide (78 mg). LCMS (ESI, m / z): [M+H] + =314.07.

[0415] 3. Synthesis of Compound 73

[0416] To a solution of N-(6-chloropyridin-3-yl)-1-methyl-N-(pyridin-3-yl)imidazol-4-carboxamide (10 mg, 0.032 mmol) and (1S,3S)-N1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclopentane-1,3-diamine (9.34 mg, 0.03 mmol) in 1,4-dioxane (1 mL), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (2 mg, 0.003 mmol) and potassium tert-butoxide (10 mg, 0.09 mmol) were added. The resulting mixture was stirred at 110 °C for 1 hour under nitrogen. The desired product was detected by LC-MS. The residue was purified by reversed-phase flash chromatography to obtain N-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-methyl-N-(pyridin-3-yl)imidazol-4-carboxamide (1.9 mg).

[0417] LCMS(ESI,m / z):[M+H] + =522.21

[0418] 1 H NMR(400MHz, Acetonitrile-d3)δ8.48(d,J=2.8Hz,1H),8.45-8.36(m,1H),8.19(s,2H),7 .91(d,J=2.8Hz,1H),7.61–7.55(m,1H),7.37–7.29(m,2H),7.26–7.20(m,2H),6.90–6.32 (m,2H),5.92(d,J=7.2Hz,1H),5.40(d,J=7.2Hz,1H),4.45–4.24(m,2H),3.61(s,3H),2.4 9(s,1H),2.29–2.18(m,2H),1.94(d,J=1.6Hz,1H),1.65–1.48(m,2H),1.40–1.28(m,1H).

[0419] Example 38

[0420] 1. Synthesis of compound a

[0421] To a mixture of 1,4-dioxane (10 mL) of 6-chloropyridin-3-amine (1.0 g, 7.7 mmol) and tert-butyl 5-bromoindole-1-carboxylate (2.7 g, 9.3 mmol), cesium carbonate (7.6 g, 23.3 mmol), tris(dibenzylacetone)dipalladium (0.7 g, 0.7 mmol), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (0.4 g, 0.7 mmol) were added. The resulting mixture was stirred at 110 °C under nitrogen for 2 hours. The residue was purified by silica gel column chromatography, eluting with dichloromethane / methanol (10 / 1) to give tert-butyl 5-[(6-chloropyridin-3-yl)amino]indole-1-carboxylate (1.0 g). LCMS (ESI, m / z): [M+H] + =344.11

[0422] 2. Synthesis of compound b

[0423] To a solution of tert-butyl 5-[(6-chloropyridin-3-yl)amino]indole-1-carboxylate (200 mg, 0.6 mmol) and cesium carbonate (568 mg, 1.7 mmol) in acetonitrile (10 mL), 1-methylimidazolium-4-carboxyl chloride (100 mg, 0.6 mmol) was added. The resulting mixture was stirred in air at 80 °C for 2 hours. The desired product was detected by LCMS. The residue was purified by silica gel column chromatography, eluting with dichloromethane / methanol (10 / 1) to give tert-butyl 5-[N-(6-chloropyridin-3-yl)1-methylimidazolium-4-amino]indole-1-carboxylate (150 mg). LCMS (ESI, m / z): [M+H] + =314.07

[0424] 3. Synthesis of Compound 74

[0425] To a solution of tert-butyl 5-[N-(6-chloropyridin-3-yl)-1-methylimidazol-4-amino]indole-1-carboxylic acid (100 mg, 0.2 mmol) and (1S,3S)-N1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclopentane-1,3-diamine (64 mg, 0.2 mmol) in 1,4-dioxane (1 mL), potassium tert-butoxide (74 mg, 0.6 mmol) and t-Buphos Pd G3 (17 mg, 0.02 mmol) were added. The resulting mixture was stirred at 110 °C under nitrogen atmosphere for 2 hours. The residue was purified by reversed-phase flash chromatography to obtain N-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-N-(1H-indol-5-yl)-1-methylimidazol-4-carboxamide (4.9 mg).

[0426] LCMS(ESI,m / z):[M+H] + =560.24

[0427] 1 H NMR(400MHz,MeOD-d4)δ8.17(s,2H),7.93–7.88(m,1H),7.51(d,J=2.0Hz,2H),7.46–7.40(m,2H),7.32(d,J=3.2Hz,1H),7.10–7.04(m,1H),6. 90–6.51(m,2H),6.48(d,J=3.2Hz,1H),6.31(s,1H),4.41–4.22(m,2H) ,3.51(s,3H),2.32–2.15(m,2H),2.07–1.90(m,2H),1.68–1.51(m,2H).

[0428] Example 39

[0429] 1. Synthesis of compound a

[0430] To a stirred solution of 6-chloropyridin-3-amine (500 mg, 3.9 mmol) and 1-(tert-butyloxycarbonyl)indole-3-carboxylic acid (1016.2 mg, 3.9 mmol) in dichloromethane (10 mL), EDCI (603.8 mg, 3.9 mmol) was added fractionally under air at room temperature. The resulting mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography to give tert-butyl-3-[(6-chloropyridin-3-yl)carbamoyl]indole-1-carboxylic acid ester (300 mg). LCMS (ESI, m / z): [M+H] + =372.30

[0431] 2. Synthesis of compound b

[0432] To a stirred solution of tert-butyl-3-[(6-chloropyridin-3-yl)carbamoyl]indole-1-carboxylic acid ester (800 mg, 2.2 mmol) and potassium tert-butoxide (241.4 mg, 2.2 mmol) in N,N-dimethylformamide (10 mL), methyl iodide (916.2 mg, 6.6 mmol) was added dropwise under air at room temperature. The resulting mixture was stirred for 30 minutes at room temperature. The residue was purified by reversed-phase rapid chromatography to give tert-butyl-3-[(6-chloropyridin-3-yl)(methyl)carbamoyl]indole-1-carboxylic acid ester (300 mg, yield 36.14%). LCMS (ESI, m / z): [M+H] + =386.30

[0433] 3. Synthesis of Compound 75

[0434] To a stirred solution of tert-butyl-3-[(6-chloropyridin-3-yl)(methyl)carbamoyl]indole-1-carboxylic acid ester (160 mg, 0.4 mmol) and (1S,3S)-N1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclopentane-1,3-diamine (101.3 mg, 0.4 mmol) in tetrahydrofuran (2 mL), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (32.9 mg, 0.04 mmol) and sodium tert-butoxide (159.4 mg, 1.7 mmol) was added fractionally at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 2 hours. The resulting mixture was then concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography to obtain N-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-N-methyl-1H-indole-3-carboxamide (2.4 mg).

[0435] LCMS(ESI,m / z):[M+H] + =494.25

[0436] 1 H NMR(400MHz,MeOD-d4)δ8.19(s,2H),8.07–7.99(m,1H),7.82(d,J=2.6Hz,1H),7.40(m,1H),7.37–7.31(m,1H),7.20–7.08(m,2H) ,6.84–6.53(m,3H),4.42–4.35(m,1H),4.31–4.25(m,1H),3.44(s,3H),2.30–2.21(m,2H),2.03–1.95(m,2H),1.64–1.54(m,2H).

[0437] Example 40

[0438] 1. Synthesis of compound a

[0439] At room temperature, HATU (8.8 g, 23.3 mmol) and diisopropylethylamine (6.0 g, 46.6 mmol) were added to a mixture of 6-chloropyridin-3-amine (2.0 g, 15.5 mmol) and 1-[(4-methoxyphenyl)methyl]pyrazol-4-carboxylic acid (4.3 g, 18.6 mmol) in N,N-dimethylformamide (25 mL). The resulting mixture was stirred at room temperature for 2 hours. The mixture was extracted with dichloromethane. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (0-50%), to give N-(6-chloropyridin-3-yl)-1-[(4-methoxyphenyl)methyl]pyrazol-4-carboxamide (1.5 g). LCMS (ESI, m / z): [M+H] + =343.09

[0440] 2. Synthesis of compound b

[0441] Sodium hydride (130 mg, 5.2 mmol) was added to a solution of N-(6-chloropyridin-3-yl)-1-[(4-methoxyphenyl)methyl]pyrazole-4-carboxamide (1.5 g, 4.3 mmol) in tetrahydrofuran (20 mL) at room temperature. The resulting mixture was stirred at room temperature for 0.5 h. Iodomethane (750 mg, 5.2 mmol) was added to the mixture. The resulting mixture was stirred at room temperature for another 1 h. The reaction was quenched with a saturated aqueous ammonium chloride solution at room temperature. The resulting mixture was extracted with dichloromethane. The organic layers were combined, washed with brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate, to give N-(6-chloropyridin-3-yl)-1-[(4-methoxyphenyl)methyl]-N-methylpyrazole-4-carboxamide (600 mg). LCMS (ESI, m / z): [M+H] + =357.10

[0442] 3. Synthesis of compound c

[0443] At room temperature and under a nitrogen atmosphere, t-BuXPhos Pd G3 (55 mg, 0.07 mmol) and t-BuOK (471 mg, 4.2 mmol) were added to a mixture of NMP (10 mL) of N-(6-chloropyridin-3-yl)-1-[(4-methoxyphenyl)methyl]-N-methylpyrazol-4-carboxamide (500 mg, 1.4 mmol) and (1S,3S)-N1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclopentane-1,3-diamine (342 mg, 1.4 mmol). The resulting mixture was stirred at 110 °C for 3 hours under a nitrogen atmosphere. The mixture was extracted with CH2Cl2. The combined organic layers were washed with saturated brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography to give N-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-[(4-methoxyphenyl)methyl]-N-methylpyrazol-4-carboxamide (180 mg). LCMS (ESI, m / z): [M+H] + =566.24.

[0444] 4. Synthesis of Compound 77

[0445] N-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-[(4-methoxyphenyl)methyl]-N-methylpyrazole-4-carboxamide (140 mg, 0.2 mmol) was stirred in TFA (2 mL) for 4 h, and the pH was adjusted to 7 with NaOH aqueous solution. The resulting mixture was extracted with ethyl acetate. The bound organic layer was washed with brine and dried on anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography to give N-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-N-methyl-1h-pyrazole-4-carboxamide (15.2 mg).

[0446] LCMS(ESI,m / z):[M+H] + =445.18

[0447] 1H NMR (400MHz, DMSO-d6) δ8.25(s,2H),7.96–7.90(m,1H),7.84(s,1H),7.58(s,1H),7.50(d,J=7.2Hz,1H),7.32(s,2H),7.20–6.9 0(m,1H),6.78(s,1H),4.32(q,J=6.8Hz,1H),4.25(s,1H),3.24(s,3H),2.22–2.06(m,2H),2.01–1.88(m,2H),1.61–1.50(m,2H).

[0448] Example 41

[0449] 1. Synthesis of compound a

[0450] HATU (4.4 g, 11.6 mmol) and DIEA (3.0 g, 23.3 mmol) were added to a DMF mixture (20 mL) of 6-chloropyridin-3-amine (1.0 g, 7.7 mmol) and 1-tert-butylcarbonylpyrazole-4-carboxylic acid (1.9 g, 9.3 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 hours and extracted with CH2Cl2. The bound organic layer was washed with brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (0-100%) to give 4-[(6-chloropyridin-3-yl)carbamoyl]pyrazole-1-carboxylic acid tert-butyl (320 mg). LCMS (ESI, m / z): [M+H] + =323.08.

[0451] 2. Synthesis of compound b

[0452] MeI (147 mg, 1.0 mmol) was added to a solution of 4-[(6-chloropyridin-3-yl)carbamoyl]pyrazole-1-carboxylic acid tert-butyl (280 mg, 0.8 mmol) and t-BuOK (194 mg, 1.7 mmol) in NMP (5 mL). The resulting mixture was stirred at 60 °C for 4 h and then extracted with CH2Cl2. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (0-70%) to give N-(6-chloropyridin-3-yl)-N,1-dimethylpyrazole-4-carboxamide (50 mg) oil. LCMS (ESI, m / z): [M+H] + =251.06

[0453] 3. Synthesis of Compound 77-1

[0454] At room temperature, t-BuXPhos Pd G3 (12 mg, 0.01 mmol) and t-BuOK (53 mg, 0.4 mmol) were added in portions to 1 mL of a mixture of N-(6-chloropyridin-3-yl)-N,1-dimethylpyrazol-4-carboxamide (40 mg, 0.1 mmol) and (1S,3S)-N1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclopentane-1,3-diamine (38 mg, 0.1 mmol) in dioxane-1,3-diamine. The resulting mixture was stirred at 110 °C for 2 hours under a nitrogen atmosphere. The mixture was extracted with dichloromethane. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography to obtain N-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-N,1-dimethylpyrazol-4-carboxamide (8.6 mg).

[0455] LCMS(ESI,m / z):[M+H] + =459.20

[0456] 1 H NMR (400MHz, DMSO-d6) δ8.23(s,2H),7.82(d,J=2.8Hz,1H),7.55(s,1H),7.47(d,J=7.2Hz,1H),7.32(dd,J=8.8,2.8Hz,1H),7.26–6.80(m,2H ),6.64(s,1H),6.52(d,J=8.8Hz,1H),4.36–4.24(m,2H),3.72(s,3H), 3.19(s,3H),2.22–2.03(m,2H),1.96–1.75(m,2H),1.58–1.44(m,2H).

[0457] Example 42

[0458] 1. Synthesis of compound a

[0459] Under a nitrogen atmosphere, a solution of N-(6-chloropyridin-3-yl)-1-[(4-methoxyphenyl)methyl]pyrazole-4-carboxamide (1.0 g, 2.9 mmol) and bromobenzene (458.0 mg, 2.9 mmol) was added to 10 mL of toluene with stirring at room temperature. XantPhos Pd G4 (280.8 mg, 0.3 mmol), XantPhos (168.81 mg, 0.292 mmol), and cesium carbonate (1.9 g, 5.8 mmol) were added in portions. The resulting mixture was stirred overnight at 110 °C. The residue was purified by reversed-phase rapid chromatography to give N-(6-chloropyridin-3-yl)-1-[(4-methoxyphenyl)methyl]-N-phenylpyrazole-4-carboxamide (480 mg). LCMS (ESI, m / z): [M+H] + =419.15.

[0460] 2. Synthesis of compound b

[0461] To a stirred solution of N-(6-chloropyridin-3-yl)-1-[(4-methoxyphenyl)methyl]-N-phenylpyrazole-4-carboxamide (100 mg, 0.2 mmol) and (1S,3S)-N1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclopentane-1,3-diamine (58.3 mg, 0.2 mmol) in tetrahydrofuran (1 mL), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (19.0 mg, 0.02 mmol) and sodium tert-butoxide (45.9 mg, 0.5 mmol) was added fractionally at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 110 °C for 3 hours. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography to obtain N-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-[(4-methoxyphenyl)methyl]-N-phenylpyrazole-4-carboxamide (70 mg).

[0462] LCMS(ESI,m / z): [M+H] + =627.50

[0463] 3. Synthesis of Compound 78

[0464] At room temperature, N-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-[(4-methoxyphenyl)methyl]-N-phenylpyrazole-4-carboxamide (160 mg, 0.3 mmol) was added in portions to 2 mL of stirred TFA. The resulting mixture was stirred at 60 °C for 2 hours. The mixture was then concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography to give N-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-N-phenyl-1H-pyrazole-4-carboxamide (13.0 mg).

[0465] LCMS(ESI,m / z):[M+H] + =507.25

[0466] 1 H NMR (400MHz, MeOD-d4) δ8.27(d,J=2.6Hz,1H),8.19(s,2H),8.15(s,1H),7.79–7.72(m,1H),7.73–7.67(m,2H),7.46(d,J=7.1 Hz,4H),6.89–6.52(m,2H),4.41(p,J=6.8Hz,1H),4.26–4.20(m,1H),2.39–2.25(m,2H),2.08–2.02(m,2H),1.69–1.62(m,2H).

[0467] Example 43

[0468] Synthesis of Compound 80

[0469] (6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)acetic acid (73 mg, 0.1 mmol) and 7-indole (22.7 mg, 0.1 mmol) were stirred in DCM (1 mL) until homogeneous. DIEA (99.5 mg, 0.7 mmol) and HATU (109.7 mg, 0.2 mmol) were added at room temperature. The resulting mixture was stirred in air at room temperature for 2 hours. The crude product (20 mg) was purified by Prep-HPLC to give 2-(6-{(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentylamino}pyridin-3-yl)-1-{pyridin[2,3-b]pyridin-1-yl}ethanecone (7.4 mg).

[0470] LCMS(ESI,m / z):[M+H] +=480.35

[0471] 1 H NMR(400MHz, Acetonitrile-d3)δ8.45(dd,J=4.8,1.6Hz,1H),8.19(s,2H),8.08– 7.96(m,3H),7.43(dd,J=8.6,2.2Hz,1H),7.31(dd,J=7.8,4.8Hz,1H),6.83–6.40 (m,3H),5.95(d,J=7.2Hz,1H),5.24(d,J=7.0Hz,1H),4.76(s,2H),4.44–4.34(m, 1H),4.33–4.24(m,1H),2.28–2.17(m,2H),1.96–1.89(m,2H),1.63–1.50(m,2H).

[0472] Example 44

[0473] Synthesis of Compound 80-1

[0474] To a solution of (6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)acetic acid (100 mg, 0.2 mmol) and 1H-pyrazol[3,4-b]pyridine (31 mg, 0.2 mmol) in dichloromethane (1 mL), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (150 mg, 0.3 mmol) and N,N-diisopropylethylamine (102 mg, 0.7 mmol) were added. The resulting mixture was stirred at room temperature in air for 2 hours. The mixture was then concentrated under reduced pressure. The product was purified by flash chromatography to obtain 2-(6-{(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-{pyrazolino[3,4-B]pyridin-1-yl}ethane ketone (18.7 mg).

[0475] LCMS(ESI,m / z): [M+H] + =481.25

[0476] 1H NMR(400MHz, Acetonitrile-d3)δ8.75–7.68(m,1H),8.33(s,1H),8.30–8.22(m,1H) ),8.19(s,2H),8.02–7.98(m,1H),7.55–7.48(m,1H),7.45–7.38(m,1H),6.84–6.41 (m,2H),6.06(d,J=7.3Hz,1H),5.76(s,1H),4.47(d,J=12.2Hz,2H),4.39(q,J=6.4H z,1H),4.33–4.27(m,1H),2.23–2.13(m,2H),1.58–1.47(m,2H),1.41–1.23(m,2H).

[0477] Example 45

[0478] Synthesis of Compound 81-1

[0479] At room temperature and in air, N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (150 mg, 0.3 mmol) and N,N-diisopropylethylamine (102 mg, 0.7 mmol) were added to a solution of (6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)acetic acid (100 mg, 0.2 mmol) and indazole (31 mg, 0.2 mmol) in dichloromethane (1 mL). The resulting mixture was stirred at room temperature and in air for 2 hours. The resulting mixture was then concentrated under reduced pressure. The product was purified by reversed-phase flash chromatography to obtain 2-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-(indazol-1-yl)acetone (21.3 mg).

[0480] LCMS(ESI,m / z): [M+H] + =480.20

[0481] 1H NMR (400MHz, DMSO-d6) δ12.32 (s, 1H), 8.56 (d, J = 0.8Hz, 1H), 8.30 (dd, J = 8.4, 1.0Hz,1H),8.24(s,2H),7.97–7.88(m,2H),7.64–7.57(m,1H),7.53(d,J=8.7H z,1H),7.51–7.36(m,2H),7.20–6.90(m,1H),6.61(d,J=8.8Hz,1H),4.41(s,2H ),4.27–4.10(m,2H),2.18–2.06(m,2H),1.95–1.83(m,2H),1.58–1.46(m,2H).

[0482] Example 46

[0483] Synthesis of Compound 85

[0484] At room temperature, N,N,N′N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (150 mg, 0.3 mmol) and N,N-diisopropylethylamine (102 mg, 0.7 mmol) were added to a solution of (6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)acetic acid (100 mg, 0.2 mmol) and pyrazole (19 mg, 0.2 mmol) in dichloromethane (1 mL). The resulting mixture was stirred in air at room temperature for 1 hour. The resulting mixture was then concentrated under reduced pressure. The product was purified by flash chromatography to obtain 2-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-(pyrazol-1-yl) acetone (26.1 mg, yield 23.06%).

[0485] LCMS(ESI,m / z): [M+H] + =430.15

[0486] 1H NMR(400MHz, Acetonitrile-d3)δ8.29(d,J=2.8Hz,1H),8.19(s,2H),7.97(d, J=2.4Hz,1H),7.81(d,J=1.5Hz,1H),7.45–7.36(m,1H),6.85–6.34(m,3H),6. 01(d,J=7.3Hz,1H),5.28(d,J=7.0Hz,1H),4.41–4.35(m,1H),4.30(s,3H),2. 29–2.15(m,2H),1.97(t,J=2.6Hz,1H),1.95–1.93(m,1H),1.63–1.44(m,2H).

[0487] Example 47

[0488] 1. Synthesis of compound a

[0489] To a solution of 5-bromo-2-chloropyridine (2.0 g, 10.4 mmol) and (4-methoxyphenyl)methanethiol (1.9 g, 12.5 mmol) in dioxane (25 mL), tris(dibenzylacetone)dipalladium (0.9 g, 1.0 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (0.6 g, 1.0 mmol), and cesium carbonate (10.1 g, 31.1 mmol) were added. The resulting mixture was stirred at 80 °C for 5 hours under a nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (7 / 1) to give 2-chloro-5-{[(4-methoxyphenyl)methyl]thio}pyridine (800 mg). LCMS (ESI, m / z): [M+H] + =266.03.

[0490] 2. Synthesis of compound b

[0491] To a solution of (1S,3S)-N1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclopentane-1,3-diamine (200 mg, 0.8 mmol) and 2-chloro-5-{[(4-methoxyphenyl)methyl]thio}pyridine (217 mg, 0.8 mmol) in dimethyl sulfoxide (4 mL), N-(2,6-dimethylphenyl)-6-hydroxypyridine-2-carboxamide (10 mg, 0.04 mmol), copper iodide (8 mg, 0.04 mmol), and potassium carbonate (452 ​​mg, 3.2 mmol) were added. The resulting mixture was stirred at 110 °C for 3 hours under a nitrogen atmosphere. The mixture was extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (5 / 1) to give (1S,3S)-N1-[5-(difluoromethoxy)pyrimidin-2-yl]-N3-(5-{[(4-methoxyphenyl)methyl]thio}pyridin-2-yl)cyclopentane-1,3-diamine (180 mg). LCMS (ESI, m / z): [M+H] + =474.17

[0492] 3. Synthesis of compound c

[0493] A solution of (1S,3S)-N1-[5-(difluoromethoxy)pyrimidin-2-yl]-N3-(5-{[(4-methoxyphenyl)methyl]thio}pyridin-2-yl)cyclopentane-1,3-diamine (140 mg, 0.3 mmol) and triethoxysilane (0.2 mL) in trifluoroacetic acid (2 mL) was stirred at 50 °C for 2 hours. The resulting mixture was extracted with dichloromethane, the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give a yellow oily substance 6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-thiol (110 mg). This crude product was used directly in the next reaction without further purification. LCMS (ESI, m / z): [M+H] + =354.11

[0494] 4. Synthesis of Compound 85-1

[0495] A solution of 6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-thiol (100 mg, 0.3 mmol) and Et3N (57 mg, 0.6 mmol) in DCM (2 mL) was mixed with pyrazol-1-carbonyl chloride (36 mg, 0.3 mmol). The resulting mixture was stirred at room temperature for 1 h and concentrated under vacuum. Purification was performed by reversed-phase flash chromatography under the following conditions: C18 silica gel column; mobile phase: acetonitrile in water (10 mmol / L NH4HCO3), gradient 0–80%, 30 min; UV detector: 254 nm. The result was [(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)sulfonyl](pyrazol-1-yl)methanecone (4.8 mg).

[0496] LCMS(ESI,m / z):[M+H] + =448.30

[0497] 1 H NMR (400MHz, DMSO-d6) δ8.41(d,J=2.8Hz,1H),8.24(s,2H),8.08(d,J=2.4Hz,1H),7.97(d,J=1.6Hz,1H),7.53–7.46(m,2H),7.25– 6.83(m,2H),6.75–6.68(m,1H),6.56(d,J=8.8Hz,1H),4.35–4.30(m,2H),2.22–2.06(m,1H),1.98–1.81(m,2H),1.62–1.43(m,2H).

[0498] Example 48

[0499] 1. Synthesis of compound a

[0500] 2-Chloro-[1,2,4]triazole[1,5-a]pyridine (1.0 g, 6.5 mmol) and tert-butyl N-[(1S,3S)-3-aminocyclopentyl]carbamate (1.3 g, 6.5 mmol) were stirred in DMSO (10 mL) at room temperature under a nitrogen atmosphere. Aliquots of N-(2,6-xylyl)-6-hydroxypyridine-2-carboxamide (94.6 mg, 0.3 mmol), CuI (49.6 mg, 0.2 mmol), and K₂CO₃ (3.6 g, 26.1 mmol) were then added. The resulting mixture was stirred at 110 °C for 2 h under a nitrogen atmosphere. Purification was performed by reversed-phase flash chromatography to obtain tert-butyl N-[(1S,3S)-3-{[1,2,4]triazole[1,5-a]pyridine-2-amino}cyclopentyl]carbamate (1.5 g).

[0501] LCMS(ESI,m / z):[M+H] + =318.25

[0502] 2. Synthesis of compound b

[0503] At room temperature, HCl was added dropwise to N-[(1S,3S)-3-{[1,2,4]triazol[1,5-a]pyridin-2-amino}cyclopentyl]carbamate (1.5 g, 4.7 mmol) dioxane (15 mL). The resulting mixture was stirred at room temperature under air for 2 hours. The mixture was then concentrated under reduced pressure to give (1S,3S)-n1-{[1,2,4]triazol[1,5-a]pyridin-2-yl}cyclopentane-1,3-diamine (1.0 g).

[0504] LCMS(ESI,m / z):[M+H] + =218.25

[0505] 3. Synthesis of compound c

[0506] A mixture of (1S,3S)-n1-{[1,2,4]triazol[1,5-a]pyridin-2-yl}cyclopentane-1,3-diamine (500 mg, 2.3 mmol) and methyl 2-(6-chloropyridin-3-yl) acetate (427.1 mg, 2.3 mmol) was stirred in DMSO (5 mL) with N-(2,6-dimethylphenyl)-6-hydroxypyridine-2-carboxamide (33.4 mg, 0.1 mmol), cuprous iodide (17.5 mg, 0.1 mmol), and potassium carbonate (1.2 g, 9.2 mmol) added at room temperature under a partial nitrogen atmosphere. The resulting mixture was stirred overnight at 110 °C under a nitrogen atmosphere. Methyl 2-(6-{(1S,3S)-3-{[1,2,4]triazol[1,5-a]pyridin-2-ylaminocyclopentyl]aminopyridin-3-yl)acetate (180 mg) was purified by reversed-phase flash chromatography. LCMS (ESI, m / z): [M+H] + =367.25

[0507] 4. Synthesis of compound d

[0508] Aliquots of LiOH·H₂O (4.1 mL, 4.1 mmol) were added to a 3 mL solution of MeOH at room temperature, along with methyl 2-(6-{(1S,3S)-3-{[1,2,4]triazol[1,5-a]pyridin-2-amino}cyclopentyl]amino}pyridin-3-yl)acetic acid (300 mg, 0.8 mmol). The resulting mixture was stirred overnight in air at room temperature. The mixture was then concentrated under reduced pressure. Purification by reversed-phase flash chromatography yielded (6-{(1S,3S)-3-{[1,2,4]triazol[1,5-a]pyridin-2-amino}cyclopentyl]amino}pyridin-3-yl)acetic acid (200 mg) as a yellow solid. LCMS (ESI, m / z): [M+H] + =353.25

[0509] 5. Synthesis of Compound 86-1

[0510] (6-{(1S,3S)-3-{[1,2,4]triazol[1,5-a]pyridin-2-ylcyclopentyl]aminopyridin-3-yl)acetic acid (70 mg, 0.2 mmol) and 3-pyrrolline (15.1 mg, 0.2 mmol) were stirred thoroughly in DCM (2 mL), and TEA (80.4 mg, 0.8 mmol) and Pybop (154.7 mg, 0.3 mmol) were added at room temperature. The resulting mixture was stirred in air at room temperature for 2 h. The mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC to give 1-(2,5-dihydropyridin-1-yl)-2-(6-{(1S,3S)-3-{[1,2,4]triazol[1,5-a]pyridin-2-amino}cyclopentyl]amino}pyridin-3-yl)acetone (4.5 mg) as a pale yellow solid.

[0511] LCMS(ESI,m / z):[M+H] + =404.40

[0512] 1 H NMR(400MHz, CDCl3-d)δ8.36–8.32(m,1H),7.78(d,J=2.4Hz,1H),7.66–7.62(m,1H),7.42 –7.37(m,2H),6.86–6.79(m,1H),6.57(d,J=8.8Hz,1H),6.27(s,1H),5.92–5.87(m,1H),5. 84–5.78(m,1H),4.90(s,1H),4.35(t,J=6.2Hz,1H),4.41–4.33(m,2H),4.33–4.28(m,2H) ,4.20–4.09(m,1H),3.50(s,2H),2.45–2.28(m,2H),2.21–2.09(m,2H),1.79–1.62(m,2H).

[0513] Example 49

[0514] Synthesis of Compound 86

[0515] Manganese dioxide (323.2 mg, 3.7 mmol) was aliquoted into a stirred solution of 1-(2,5-dihydropyridin-1-yl)-2-(6-{(1S,3S)-3-{[1,2,4]triazol[1,5-a]pyridin-2-ylaminocyclopentyl]aminopyridin-3-yl) acetone (50 mg, 0.1 mmol) in DCM (2 mL). The resulting mixture was stirred overnight in air at room temperature and concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography to give 1-(pyridin-1-yl)-2-(6-{(1S,3S)-3-{[1,2,4]triazol[1,5-a]pyridin-2-ylaminocyclopentyl]aminopyridin-3-yl) acetone (1.2 mg).

[0516] LCMS(ESI,m / z):[M+H] + =402.35

[0517] 1 H NMR(400MHz, CDCl3-d)δ8.35(d,J=6.6Hz,1H),7.85(d,J=2.4Hz,1H),7.62– 7.54(m,1H),7.45–7.34(m,4H),6.97(s,1H),6.86–6.79(m,1H),6.62(d,J= 9.0Hz,1H),6.39–6.32(m,2H),4.87(s,1H),4.36(s,1H),4.19(t,J=6.6Hz, 1H),4.04(s,2H),2.44–2.31(m,2H),2.27–2.09(m,2H),1.78–1.65(m,2H).

[0518] Example 50

[0519] 1. Synthesis of compound a

[0520] 2-Bromo-5h,6H,7H,8H-[1,2,4]triazole[1,5-a]pyridine (1.0 g, 5.0 mmol) and tert-butyl N-[(1S,3S)-3-aminocyclopentyl]carbamate (991.2 mg, 5.0 mmol) were added to DMSO (10 mL) along with N-(2,6-dimethylphenyl)-6-hydroxypyridine-2-carboxamide (71.9 mg, 0.3 mmol), cuprous iodide (37.7 mg, 0.2 mmol), and potassium carbonate (2.7 g, 19.8 mmol). The resulting mixture was stirred at 110 °C for 2 hours under a nitrogen atmosphere. Purified by reversed-phase flash chromatography, N-[(1S,3S)-3-{5H,6H,7H,8H-[1,2,4]triazole[1,5-a]pyridine-2-amino}cyclopentyl]carbamate tert-butyl (600 mg) was obtained. LCMS (ESI, m / z): [M+H] + =322.25

[0521] 2. Synthesis of compound b

[0522] At room temperature, 1,4-dioxane hydrochloride (6 mL) was added dropwise to N-[(1S,3S)-3-{5H,6H,7H,8H-[1,2,4]triazol[1,5-a]pyridin-2-yl}cyclopentyl]carbamate (600 mg, 1.8 mmol). The resulting mixture was stirred in air at room temperature for 2 hours. The mixture was then concentrated under reduced pressure. The result was (1S,3S)-n1-{5H,6H,7H,8H-[1,2,4]triazol[1,5-a]pyridin-2-yl}cyclopentane-1,3-diamine (400 mg). LCMS (ESI, m / z): [M+H] + =222.25

[0523] 3. Synthesis of compound c

[0524] A mixture of (1S,3S)-n1-{5H,6H,7H,8H-[1,2,4]triazol[1,5-a]pyridin-2-yl}cyclopentane-1,3-diamine (500 mg, 2.2 mmol) and methyl 2-(6-chloropyridin-3-yl) acetate (419.3 mg, 2.2 mmol) was stirred in DMSO (5 mL) with N-(2,6-dimethylphenyl)-6-hydroxypyridine-2-carboxamide (32.8 mg, 0.1 mmol), cuprous iodide (17.2 mg, 0.1 mmol), and potassium carbonate (1.2 g, 9.1 mmol) added at room temperature under a partial nitrogen atmosphere. The resulting mixture was stirred overnight at 110 °C under a nitrogen atmosphere. Methyl 2-(6-{(1S,3S)-3-{5H,6H,7H,8H-[1,2,4]triazol[1,5-a]pyridin-2-ylaminocyclopentyl]aminopyridin-3-yl)acetate (180 mg) was purified by reversed-phase flash chromatography. LCMS (ESI, m / z): [M+H] + =371.25

[0525] 4. Synthesis of compound d

[0526] LiOH·H₂O (2.4 mL, 2.4 mmol) was added at room temperature to a solution of methyl 2-(6-{(1S,3S)-3-{5H,6H,7H,8H-[1,2,4]triazol[1,5-a]pyridin-2-aminocyclopentyl]aminopyridin-3-yl)acetate (180 mg, 0.5 mmol) in MeOH (1.8 mL) and water (2 mL). The resulting mixture was stirred at room temperature under air for 2 hours. The mixture was concentrated under reduced pressure. The residue was acidified with HCl to pH 2. Purification was performed by reversed-phase flash chromatography to give (6-{(1S,3S)-3-{5H,6H,7H,8H-[1,2,4]triazol[1,5-a]pyridin-2-aminocyclopentyl]aminopyridin-3-yl)acetic acid (120 mg). LCMS (ESI, m / z): [M+H] + =357.25

[0527] 5. Synthesis of Compound 87-1

[0528] (6-{(1S,3S)-3-{5H,6H,7H,8H-[1,2,4]triazol[1,5-a]pyridin-2-ylaminocyclopentyl]aminopyridin-3-yl)acetic acid (50 mg, 0.1 mmol) and 3-pyrrolline (10.6 mg, 0.1 mmol) were stirred thoroughly in a DCM (2 ml) solution. DIEA (72.5 mg, 0.5 mmol) and HATU (80.1 mg, 0.2 mmol) were added at room temperature. The resulting mixture was stirred in air at room temperature for 2 hours. The mixture was then concentrated under reduced pressure. The crude product (30 mg) was purified by Prep-HPLC. Column type: Xselect CSH C185 μm, 30 mm x 150 mm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient (B%): 3% B to 13% B over 7 min; wavelength: 254 nm / 220 nm; RT1 (min): 6.48. 1-(2,5-dihydropyridin-1-yl)-2-(6-{(1S,3S)-3-{5H,6H,7H,8H-[1,2,4]triazol[1,5-a]pyridin-2-amino}cyclopentyl]aminopyridin-3-yl) acetone (11.3 mg) was a pale yellow solid.

[0529] LCMS(ESI,m / z):[M+H] + =408.40

[0530] 1 H NMR (400MHz, DMSO-d6) δ7.85–7.73(m,1H),7.26–7.20(m,1H),6.39(t,J=7.6Hz, 2H),5.90(s,2H),5.65(d,J=7.2Hz,1H),4.30(t,J=4.1Hz,2H),4.24–4.14(m,1H ),4.06(t,J=4.0Hz,2H),3.98–3.88(m,1H),3.83(t,J=5.8Hz,2H),3.43(s,2H), 2.61(t,J=6.2Hz,2H),2.14–1.98(m,2H),1.96–1.67(m,6H),1.51–1.31(m,2H).

[0531] Example 51

[0532] Manganese dioxide (213.3 mg, 2.4 mmol) was aliquoted into a stirred solution of 1-(2,5-dihydropyridin-1-yl)-2-(6-{(1S,3S)-3-{5H,6H,7H,8H-[1,2,4]triazol[1,5-a]pyridin-2-ylaminocyclopentyl]aminopyridin-3-yl)acetone (50 mg, 0.1 mmol) in DCM (2 mL). The resulting mixture was stirred overnight in air at 45 °C. The mixture was then concentrated under reduced pressure. The crude product (30 mg) was purified by Prep-HPLC to obtain 1-(pyridin-1-yl)-2-(6-{(1S,3S)-3-{5H,6H,7H,8H-[1,2,4]triazol[1,5-a]pyridin-2-ylaminocyclopentyl]aminopyridin-3-yl) acetone (2.5 mg).

[0533] LCMS(ESI,m / z):[M+H] + =406.35

[0534] 1 H NMR(400MHz, Acetonitrile-d3)δ7.87(d,J=2.4Hz,1H),7.56–7.50(m,1H),7.46– 7.41(m,2H),6.65(d,J=8.8Hz,1H),6.40(s,1H),6.35(t,J=2.4Hz,2H),4.71(s,1H ),4.30(s,1H),4.13(s,2H),4.07(t,J=6.6Hz,1H),3.89(t,J=5.8Hz,2H),2.70(s ,2H),2.29–2.15(m,3H),2.06–2.00(m,2H),1.93–1.83(m,3H),1.62–1.52(m,2H).

[0535] Example 52

[0536] Synthesis of Compound 91-1

[0537] 3-Bromo-1-methyl-1,2,4-triazole (100 mg, 0.6 mmol) and 2-(6-{(1S,3S)-3-aminocyclopentyl]aminopyridin-3-yl)-1-(2,5-dihydropyridin-1-yl)acetone (176.8 mg, 0.6 mmol) were stirred in tetrahydrofuran (2 mL), followed by the addition of GPhos Pd G6 TES (58.3 mg, 0.06 mmol) and sodium trimethylsilicate (277 mg, 2.5 mmol) in portions under a nitrogen atmosphere at room temperature. The resulting mixture was stirred overnight at 50 °C under a nitrogen atmosphere. The mixture was then concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography to obtain 1-(2,5-dihydropyridin-1-yl)-2-(6-{(1S,3S)-3-[(1-methyl-1,2,4-triazol-3-yl)amino]cyclopentyl]aminopyridin-3-yl) acetone (13.3 mg).

[0538] LCMS(ESI,m / z):[M+H] + =368.35

[0539] 1 H NMR(400MHz,DMSO-d6)δ7.92(s,1H),7.80(s,1H),7.31–7.17(m,1H),6.41( d,J=8.2Hz,2H),5.90(s,2H),5.80(d,J=7.1Hz,1H),4.30(t,J=4.2Hz,2H), 4.25–4.15(m,1H),4.06(t,J=4.0Hz,2H),4.00–3.89(m,1H),3.63(s,3H),2 .14–1.98(m,2H),1.90–1.81(m,1H),1.81–1.71(m,1H),1.52–1.34(m,2H).

[0540] Example 53

[0541] Synthesis of Compound 91

[0542] Manganese dioxide (709.7 mg, 8.1 mmol) was aliquoted into a stirred solution of 1-(2,5-dihydropyridin-1-yl)-2-(6-{(1S,3S)-3-[(1-methyl-1,2,4-triazol-3-yl)amino]cyclopentyl]aminopyridin-3-yl)acetone (100 mg, 0.3 mmol) in DCM (3 mL). The resulting mixture was stirred overnight in air at room temperature. The mixture was filtered, and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The crude product (60 mg) was purified by Prep-HPLC to give 2-(6-{(1S,3S)-3-[(1-methyl-1,2,4-triazol-3-yl)amino]cyclopentyl]amino}pyridin-3-yl)-1-(pyrrolo-1-yl)acetone (3.3 mg).

[0543] LCMS(ESI,m / z):[M+H] + =366.35

[0544] 1 H NMR (400MHz, CDCl3-d) δ8.35(s,1H),7.86(d,J=2.4Hz,1H),7.66(s,1H),7.56–7.50(m,1H),7.37(t,J=2.3Hz,2H),6.79(s,1H),6.53(d,J =8.8Hz,1H),6.34(t,J=2.4Hz,2H),4.21–4.09(m,2H),4.02(s,2H),3.76(s,3H),2.37–2.26(m,2H),2.14–1.99(m,2H),1.69–1.57(m,2H).

[0545] Example 54

[0546] Synthesis of Compound 98

[0547] Manganese dioxide (610.0 mg, 7.0 mmol) was added in portions to a stirred solution of N-(3-{[(1S,3S)-3-({5-[2-(2,5-dihydropyrrolo-1-yl)-2-oxoethyl]pyridin-2-yl}amino)cyclopentyl]amino}-1,2,4-thiadiazol-5-yl)acetamide (100 mg, 0.2 mmol) under air at 60 °C. The resulting mixture was stirred at room temperature for 2 days. The mixture was filtered, and the filter cake was washed with 1,2-dichloroethane. The filtrate was concentrated under reduced pressure. The resulting mixture was then concentrated under reduced pressure. The crude product (mg) was purified by preparative high performance liquid chromatography to obtain N-(3-{[(1S,3S)-3-({5-[2-oxo-2-(pyrrolo-1-yl)ethyl]pyridin-2-yl}amino)cyclopentyl]amino}-1,2,4-thiadiazol-5-yl)acetamide (1.7 mg, 1.71% yield).

[0548] LCMS(ESI,m / z):[M+H] + =426.15

[0549] 1 H NMR (400MHz, DMSO-d6) δ7.90(d,J=2.3Hz,1H),7.56–7.51(m,2H),7.35–7.28(m,1H),6.94(d,J=7.2Hz,1H),6.49(d,J=6.8Hz,1H),6.42(d,J=8 .6Hz,1H),6.33(t,J=2.3Hz,2H),4.26–4.20(m,1H),4.18–4.08(m,3H) ,2.18(s,3H),2.13–2.08(m,2H),1.93–1.81(m,2H),1.54–1.40(m,2H).

[0550] Example 55

[0551] 1. Synthesis of compound a

[0552] A solution of 3-bromo-5-chloro-1,2,4-thiadiazole (5 g, 25.069 mmol) in ethanol (15 mL) was stirred under air at room temperature, and ammonia (1.76 g, 50.138 mmol) was added dropwise. The resulting mixture was stirred at 70 °C for 3 hours under air. The mixture was then concentrated under reduced pressure. The desired product was detected by liquid chromatography-mass spectrometry, yielding 3-bromo-1,2,4-thiadiazole-5-amine (3.0 g). LCMS (ESI, m / z): [M+H] + =179.95

[0553] 2. Synthesis of compound b

[0554] Acetyl chloride (13.1 g, 166.7 mmol) was added dropwise to a stirred solution of 3-bromo-1,2,4-thiadiazol-5-amine (2.0 g, 11.1 mmol) and triethylamine (11.2 g, 111.1 mmol) in dichloromethane (20 mL) under air at 0 °C. The resulting mixture was stirred at room temperature for 30 min under air. The desired product was detected by liquid chromatography-mass spectrometry. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (4:1) to give N-(3-bromo-1,2,4-thiadiazol-5-yl)acetamide (1.0 g), LCMS (ESI, m / z): [M+H] + =221.80.

[0555] 3. Synthesis of Compound 98-1

[0556] To a stirred solution of N-(3-bromo-1,2,4-thiadiazol-5-yl)acetamide (50 mg, 0.2 mmol) and 2-(6-{[(1S,3S)-3-aminocyclopentyl]amino}pyridin-3-yl)-1-(2,5-dihydropyrrolo-1-yl)acetone (64.5 mg, 0.2 mmol) in tetrahydrofuran (1 mL), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (17.9 mg, 0.02 mmol) and sodium tert-butoxide (86.6 mg, 0.9 mmol) were added fractionally at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 2 hours. The mixture was filtered, and the filter cake was washed with acetonitrile. The filtrate was concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography to obtain N-(3-{[(1S,3S)-3-({5-[2-(2,5-dihydropyrrolo-1-yl)-2-oxoethyl]pyridin-2-yl}amino)cyclopentyl]amino}-1,2,4-thiadiazol-5-yl)acetamide (2.3 mg, 2.39% yield).

[0557] LCMS(ESI,m / z): [M+H] + =428.20

[0558] 1H NMR(400MHz, DMSO-d6)δ7.80(d,J=2.3Hz,1H),7.25–7.20(m,1H),6.95(s,1H),6.43–6.38(m,2H),5.91(s,2H),4.30(d,J=4.1Hz,2H),4.22(d, J=7.0Hz,1H),4.14(d,J=6.9Hz,1H),4.07(d,J=4.3Hz,2H),3.43(s,2H) ,2.18(s,3H),2.12–2.07(m,2H),1.93-1.79(m,2H),1.52-1.42(m,2H).

[0559] Example 56

[0560] 1. Synthesis of compound a

[0561] Diisopropylethylamine (709 mg, 5.4 mmol) was added to a solution of 3,6-dichloro-5-methyl-1,2,4-triazine (300 mg, 1.8 mmol) and 2-(6-{[(1S,3S)-3-aminocyclopentyl]amino}pyridin-3-yl)-1-(2,5-dihydropyrrolo-1-yl)acetone (628 mg, 2.1 mmol) in dimethyl sulfoxide (5 mL). The resulting mixture was stirred in air at 120 °C for 2 hours. The desired product was detected by LCMS. The residue was purified by silica gel column chromatography, eluting with dichloromethane / methanol (12:1) to give 2-(6-{[(1S,3S)-3-[(6-chloro-5-methyl-1,2,4-triazin-3-yl)amino]cyclopentyl]amino}pyridin-3-yl)-1-(2,5-dihydropyrrolo-1-yl)acetone (168 mg). LCMS (ESI, m / z): [M+H] + =414.17

[0562] 2. Synthesis of compound b

[0563] Pd(dppf)Cl2 (53 mg, 0.07 mmol) was added to a methanol (1 mL) solution of 2-(6-{[(1S,3S)-3-[(6-chloro-5-methyl-1,2,4-triazin-3-yl)amino]cyclopentyl]amino}pyridin-3-yl)-1-(2,5-dihydropyrrolo-1-yl)acetone (300 mg, 0.7 mmol). The resulting mixture was stirred overnight at 100 °C under a carbon monoxide atmosphere. The desired product was detected by LCMS. The resulting mixture was filtered, and the filter cake was washed with dichloromethane. The filtrate was concentrated under reduced pressure. 3-{[(1S,3S)-3-({5-[2-(2,5-dihydropyrrolo-1-yl)-2-oxoethyl]pyridin-2-yl}amino)cyclopentyl}amino}-5-methyl-1,2,4-triazine-6-carboxylic acid methyl ester (200 mg) was obtained as a brown solid. LCMS (ESI, m / z): [M+H] + =438.33

[0564] 3. Synthesis of Compound 114-1

[0565] In a 40 mL volumetric flask, methyl 3-{[(1S,3S)-3-({5-[2-(2,5-dihydropyrrolo-1-yl)-2-oxoethyl]pyridin-2-yl}amino)cyclopentyl]amino}-5-methyl-1,2,4-triazine-6-carboxylate (200 mg, 0.4 mmol) and ethylamine (30-35%, in ethanol) (2 mL) were added. The resulting mixture was stirred at 80 °C for 2 hours. The desired product was detected by LCMS. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography to obtain 3-{[(1S,3S)-3-({5-[2-(2,5-dihydropyrrolo-1-yl)-2-oxoethyl]pyridin-2-yl}amino)cyclopentyl]amino}-N-ethyl-5-methyl-1,2,4-triazine-6-carboxamide (4.2 mg).

[0566] LCMS(ESI,m / z):[M+H] + =451.25

[0567] 1H NMR(400MHz,MeOD-d4)δ7.83(d,J=2.4Hz,1H),7.49–7.43(m,1H),6.63(d,J=8. 8Hz,1H),5.95–5.88(m,2H),4.58(d,J=11.2Hz,2H),4.45–4.40(m,2H),4.35–4. 28(m,1H),4.25–4.20(m,2H),3.60(s,2H),3.43(q,J=7.2Hz,2H),2.65(s,3H), 2.39–2.24(m,2H),2.17–1.97(m,2H),1.78–1.51(m,2H),1.24(t,J=7.2Hz,3H).

[0568] Example 57

[0569] Synthesis of Compound 114

[0570] Under air atmosphere, manganese dioxide (96 mg, 1.1 mmol) was added to a stirred solution of 3-{[(1S,3S)-3-({5-[2-(2,5-dihydropyrrolo-1-yl)-2-oxoethyl]pyridin-2-yl}amino)cyclopentyl]amino}-N-ethyl-5-methyl-1,2,4-triazin-6-carboxamide (100 mg, 0.2 mmol) in dichloromethane (1 mL). The resulting mixture was stirred in air at room temperature for 72 hours. The desired product was detected by LCMS. The mixture was filtered, the filtrate was evaporated to dryness, and the residue was purified by high performance liquid chromatography to give N-ethyl-5-methyl-3-{[(1S,3S)-3-({5-[2-oxo-2-(pyrrolo-1-yl)ethyl]pyridin-2-yl}amino)cyclopentyl]amino}-1,2,4-triazin-6-carboxamide (4.9 mg).

[0571] LCMS(ESI,m / z):[M+H] + =449.23

[0572] 1H NMR (400MHz, MeOD-d4) δ7.90(d,J=2.4Hz,1H),7.48(t,J=2.4Hz,2H),7.45–7.40(m,1H),6.56(d,J=8.8Hz,1H),6.33(t,J=2.4Hz,2H),4.57(s,1H),4. 33(q,J=6.6Hz,1H),4.13(s,2H),3.43(q,J=7.2Hz,2H),2.65(s,3H),2.34 –2.23(m,2H),2.20–1.95(m,2H),1.76–1.52(m,2H),1.24(t,J=7.2Hz,3H).

[0573] Example 58

[0574] 1. Synthesis of compound a

[0575] Ethyl 2-chloro-4,6-dimethylpyrimidin-5-carboxylate (200 mg, 0.9 mmol) and 2-(6-{(1S,3S)-3-aminocyclopentyl]aminopyridin-3-yl)-1-(2,5-dihydropyridin-1-yl)acetone (266.8 mg, 0.9 mmol) were stirred thoroughly in DMF (5 mL), and potassium carbonate (515 mg, 3.7 mmol) was added at room temperature. The resulting mixture was stirred overnight in air at 50 °C. Purification was performed by reversed-phase flash chromatography to give ethyl 2-[(1S,3S)-3-({5-[2-(2,5-dihydropyrrolo-1-yl)-2-oxoethyl]pyridin-2-yl}amino)cyclopentyl]amino}-4,6-dimethylpyrimidin-5-carboxylate (200 mg). LCMS (ESI, m / z): [M+H] + =465.25.

[0576] 2. Synthesis of compound b

[0577] Ethyl 2-{(1S,3S)-3-({5-[2-(2,5-dihydropyrrolo-1-yl)-2-oxoethyl]pyridin-2-yl}amino)cyclopentyl]amino}-4,6-dimethylpyrimidin-5-carboxylic acid (120 mg, 0.2 mmol) was stirred in methanol (2 mL), and LiOH·H₂O (1.3 mL, 1.3 mmol) was added dropwise at room temperature. The resulting mixture was stirred in air at room temperature for 2 h. The mixture was concentrated under reduced pressure. The mixture was acidified to pH 2 with an aqueous solution of hydrochloric acid. It was purified by reversed-phase flash chromatography to give 2-{(1S,3S)-3-({5-[2-(2,5-dihydropyrrolo-1-yl)-2-oxoethyl]pyridin-2-yl}amino)cyclopentyl]amino}-4,6-dimethylpyrimidin-5-carboxylic acid (80 mg) as a yellow solid. LCMS(ESI,m / z):[M+H] + =437.25

[0578] 3. Synthesis of Compound 117-1

[0579] 2-{(1S,3S)-3-({5-[2-(2,5-dihydropyrrolo-1-yl)-2-oxoethyl]pyridin-2-yl}amino)cyclopentyl]amino}-4,6-dimethylpyrimidin-5-carboxylic acid (40 mg, 0.1 mmol) and methylamine hydrochloride (9.2 mg, 0.1 mmol) were stirred thoroughly in a DCM (2 mL), and DIEA (59.2 mg, 0.5 mmol) and HATU (52.2 mg, 0.1 mmol) were added at room temperature. The resulting mixture was stirred in air at room temperature for 2 h. The crude product (20 mg) was purified by Prep-HPLC to give 2-{[(1S,3S)-3-({5-[2-(2,5-dihydropyrrolo-1-yl)-2-oxoethyl]pyridin-2-yl}amino)cyclopentyl]amino}-n,4,6-trimethylpyrimidin-5-carboxamide (3.4 mg).

[0580] LCMS(ESI,m / z):[M+H] + =450.45

[0581] 1H NMR(400MHz, CDCl3-d)δ7.73(s,1H),7.71–7.62(m,1H),6.68(d,J=9.0Hz,2 H),6.30–6.20(m,1H),5.93–5.87(m,1H),5.86–5.80(m,1H),5.77(d,J=6.8H z,1H),4.54–4.42(m,1H),4.37–4.21(m,4H),4.16–4.06(m,1H),3.50(s,2H ),2.99(d,J=4.8Hz,3H),2.32(s,8H),2.10–1.99(m,2H),1.77–1.49(m,2H).

[0582] Example 59

[0583] Synthesis of Compound 117

[0584] 2-{(1S,3S)-3-({5-[2-(2,5-dihydropyrrolo-1-yl)-2-oxoethyl]pyridin-2-yl}amino)cyclopentyl]amino}-n,4,6-trimethylpyrimidine-5-carboxamide (40 mg, 0.09 mmol) was stirred in dichloromethane (2 mL), and manganese dioxide (232 mg, 2.6 mmol) was added at room temperature. The resulting mixture was stirred in air at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The crude product (20 mg) was purified by Prep-HPLC to give N,4,6-trimethyl-2-{(1S,3S)-3-({5-[2-oxo-2-(pyrrolo-1-yl)ethyl]pyridin-2-yl}amino)cyclopentyl]aminopyrimidine-5-carboxamide (3.1 mg).

[0585] LCMS(ESI,m / z):[MH] - =446.35

[0586] 1 H NMR (400MHz, CDCl3-d) δ7.86(s,1H),7.55(d,J=8.8Hz,1H),7.37(s,2H),6.75(s,1H),6.56(d,J=8.8Hz,1H),6.35(s,2H),5.84–5.59(m ,2H),4.52(q,J=6.7Hz,1H),4.23–4.09(m,1H),4.03(s,2H),3.02(d,J=4.8Hz,3H),2.34(s,8H),2.13–1.97(m,2H),1.76–1.50(m,2H).

[0587] Example 60

[0588] 1. Synthesis of Compound 17-8

[0589] 2-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-(2,5-dihydropyridin-1-yl)acetone (150 mg, 0.3 mmol) was stirred in methanol (2 mL) and Pd / C (30 mg) was added at room temperature. The resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere. The mixture was filtered, and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure. The crude product (50 mg) was purified by Prep-HPLC to give 2-(6-{(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-(pyridin-1-yl)acetone; formic acid (13.2 mg).

[0590] LCMS(ESI,m / z):[M+H] + =433.30

[0591] 1 H NMR (400MHz, DMSO-d6) δ12.78(s,1H),8.23(s,2H),8.15(s,1H),7.78(d,J=2.4Hz,1H),7.45(d,J=7.2Hz,1H),7.25–6.84(m,2H),6.40(d,J=8.2Hz, 2H),4.34–4.17(m,2H),3.46(t,J=6.8Hz,2H),3.27(t,J=12.0Hz,2H),2. 15–2.04(m,2H),1.94–1.81(m,4H),1.80–1.71(m,2H),1.58–1.39(m,2H).

[0592] Example 61

[0593] 1. Synthesis of compound a

[0594] 6-Chloropyridin-3-amine (1.0 g, 7.7 mmol) and iodobenzene (1.6 g, 7.7 mmol) were added to 1,4-dioxane (10 mL), and Pd₂(dba)₃ (0.7 g, 0.7 mmol) and xantphos (0.4 g, 0.7 mmol) were added to air at room temperature. The resulting mixture was stirred overnight at 110 °C under nitrogen. The desired product was detected by LCMS. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (10:1) to give a yellow solid 6-chloro-N-phenylpyridin-3-amine (750 mg). LCMS (ESI, m / z): [M+H] + =205.05

[0595] 2. Synthesis of compound b

[0596] At room temperature, 1-methylimidazolium-4-carboxyl chloride (254 mg, 1.7 mmol) was added to a mixture of 6-chloro-N-phenylpyridin-3-amine (300 mg, 1.4 mmol) and cesium carbonate (1.4 g, 4.3 mmol) in acetonitrile (5 mL). The resulting mixture was stirred in air at 80 °C for 2 hours. The desired product was detected by LCMS. The residue was purified by reversed-phase flash chromatography to N-(6-chloropyridin-3-yl)-1-methyl-N-phenylimidazolium-4-carboxamide (100 mg) as a brown solid.

[0597] LCMS(ESI,m / z): [M+H] + =313.08

[0598] 3. Synthesis of Compound 73-1

[0599] Cesium carbonate (312 mg, 0.9 mmol) and 3-chloropyridine; {1,3-bis[2,6-bis(heptane-4-yl)phenyl]-4,5-dichloro-2,3-dihydro-1H-imidazol-2-yl}dichloropalladium (31 mg, 0.03 mmol) were added to a mixture of N-(6-chloropyridin-3-yl)-1-methyl-N-phenylimidazol-4-carboxamide (100 mg, 0.3 mmol) and (1S,3S)-N1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclopentane-1,3-diamine (78 mg, 0.3 mmol) in 1,4-dioxane (1 mL). The resulting mixture was stirred overnight at 110 °C under nitrogen atmosphere. The desired product was detected by LCMS. The residue was purified by reversed-phase flash chromatography to obtain N-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-methyl-N-phenylimidazol-4-carboxamide (16.4 mg).

[0600] LCMS(ESI,m / z):[M+H] + =521.21

[0601] 1 H NMR (400MHz, DMSO-d6) δ8.23(s,2H),7.79(d,J=2.8Hz,1H),7.48–7.41(m,2H),7.37–7.28(m,2H),7.27–6.70(m,6H),6.68(d,J=6. 8Hz,1H),6.42(d,J=8.8Hz,1H),4.38–4.18(m,2H),3.57(s,3H),2.15–2.04(m,2H),1.93–1.76(m,J=7.2Hz,2H),1.56–1.41(m,1H).

[0602] Example 62

[0603] 1. Synthesis of compound a

[0604] To a stirred solution of 5-bromo-2-methyl-1H-indole (10.0 g, 47.6 mmol) and di-tert-butyl dicarbonate (10.4 g, 47.6 mmol) in acetonitrile (150 mL), 4-dimethylaminopyridine (7.0 g, 57.1 mmol) was added fractionally under ambient air at room temperature. The resulting mixture was stirred overnight under ambient air at room temperature. The desired product was detected by liquid chromatography-mass spectrometry. The resulting mixture was concentrated under reduced pressure. The reaction mixture was diluted with ethyl acetate (300 mL), and the organic solution was washed successively with water, 1 mol / L hydrochloric acid solution, saturated sodium bicarbonate solution, and brine. The residue was purified by reversed-phase rapid chromatography to give tert-butyl 5-bromo-2-methylindole-1-carboxylic acid ester (12.0 g). LCMS (ESI, m / z): [M+H] + =310.10

[0605] 2. Synthesis of compound b

[0606] Under a nitrogen atmosphere, at room temperature, Pd2(dba)3 (356.2 mg, 0.4 mmol) and XPhos (370.8 mg, 0.8 mmol), sodium tert-butoxide (1.1 g, 11.7 mmol) were added to a stirred mixture of 6-chloropyridin-3-amine (1.0 g, 7.8 mmol) and tert-butyl-5-bromo-2-methylindole-1-carboxylic acid ester (2.9 g, 9.3 mmol) in dioxane (20 mL). The resulting mixture was stirred at 90 °C for 2 hours under a nitrogen atmosphere. The desired product was detected by liquid chromatography-mass spectrometry. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (8:1) to give tert-butyl-5-[(6-chloropyridin-3-yl)amino]-2-methylindole-1-carboxylic acid ester (1.36 g). LCMS (ESI, m / z): [M+H] + =358.05

[0607] 3. Synthesis of compound c

[0608] To a stirred solution of tert-butyl 5-[(6-chloropyridin-3-yl)amino]-2-methylindole-1-carboxylate (50 mg, 0.1 mmol) and cesium carbonate (136.58 mg, 0.4 mmol) in acetonitrile (2 mL), 1-methylimidazolium-4-carboxyl chloride (24.2 mg, 0.2 mmol) was added fractionally at room temperature. The resulting mixture was stirred at 80 °C for 2 hours in air. The desired product was detected by liquid chromatography-mass spectrometry. The resulting mixture was filtered, and the filter cake was washed with acetonitrile. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid column chromatography to give tert-butyl 5-[N-(6-chloropyridin-3-yl)-1-methylimidazolium-4-amide]-2-methylindole-1-carboxylate (200 mg). LCMS (ESI, m / z): [M+H] + =466.1

[0609] 4. Synthesis of Compound 74-1

[0610] To a stirred solution of tert-butyl-5-[N-(6-chloropyridin-3-yl)-1-methylimidazol-4-amide]-2-methylindole-1-carboxylic acid ester (200 mg, 0.4 mmol) and (1S,3S)-N1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclopentane-1,3-diamine (104.8 mg, 0.4 mmol) in THF (3 mL), t-BuXPhos Pd G3 (34.1 mg, 0.04 mmol) and sodium tert-butoxide (165.0 mg, 1.7 mmol) were added fractionally at room temperature under a nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with MeCN. The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC to obtain N-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-methyl-N-(2-methyl-1H-indol-5-yl)imidazol-4-carboxamide (8.9 mg).

[0611] LCMS(ESI,m / z): [M+H] + =572.30

[0612] 1H NMR (400MHz, DMSO-d6) δ10.97(s,1H),8.23(s,2H),7.82(q,J=2.5Hz,1H),7.54–7.35(m,2H),7.32–7.03(m,4H),6.95–6.81(m,2H),6.68–6.54 (m,1H),6.49–6.36(m,1H),6.08(s,1H),4.34–4.20(m,2H),3.50(s,3H) ,2.37(s,3H),2.17–2.04(m,2H),1.91–1.69(m,2H),1.56–1.42(m,2H).

[0613] Example 63

[0614] 1. Synthesis of compound a

[0615] To a stirred solution of 1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (5.0 g, 30.8 mmol) and dimethylaminopyridine (DMAP) (5.7 g, 46.3 mmol) in acetonitrile (50 mL), tert-butyloxycarbonyl chloride (Boc₂O) (7.4 g, 33.9 mmol) was added fractionally under air at room temperature. The resulting mixture was stirred overnight at room temperature. The desired product was detected by liquid chromatography-mass spectrometry (LCMS). The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid column chromatography to give crude 1-(tert-butyloxycarbonyl)pyrrolo[3,2-b]pyridine-3-carboxylic acid (2.5 g). LCMS (ESI, m / z): [M+H] + =263.25.

[0616] 2. Synthesis of compound b

[0617] To a stirred solution of 1-(tert-butyloxycarbonyl)pyrrolo[3,2-b]pyridine-3-carboxylic acid (9.8 g, 37.4 mmol) and 6-chloropyridine-3-amine (4.8 g, 37.4 mmol) in dichloromethane (100 mL), EDCI (8.7 g, 56.1 mmol) was added fractionally at room temperature under air. The resulting mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography to give a white solid, tert-butyl-3-[(6-chloropyridin-3-yl)carbamoyl]pyrrolo[3,2-b]pyridine-1-carboxylate (2.1 g). LCMS (ESI, m / z): [M+H] + =373.25

[0618] 3. Synthesis of compound c

[0619] To a stirred solution of 1-(tert-butyloxycarbonyl)pyrrolo[3,2-b]pyridine-3-carboxylic acid (9.8 g, 37.4 mmol) and 6-chloropyridine-3-amine (4.8 g, 37.4 mmol) in dichloromethane (100 mL), EDCI (8.7 g, 56.1 mmol) was added fractionally at room temperature under air. The resulting mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography to give a white solid, tert-butyl-3-[(6-chloropyridin-3-yl)carbamoyl]pyrrolo[3,2-b]pyridine-1-carboxylate (2.1 g). LCMS (ESI, m / z): [M+H] + =387.25

[0620] 4. Synthesis of compound d

[0621] To a hydrochloric acid solution containing 1,4-dioxane (4.0 M) (5 mL) and methanol (5 mL) under stirring, tert-butyl 3-[(6-chloropyridin-3-yl)(methyl)carbamoyl]pyrrolo[3,2-b]pyridine-1-carboxylate (600 mg, 1.6 mmol) was added in portions under air at room temperature. The resulting mixture was stirred for 1 hour at room temperature. The mixture was then concentrated under vacuum to give a white solid N-(6-chloropyridin-3-yl)-N-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (500 mg).

[0622] LCMS(ESI,m / z): [M+H] + =287.25

[0623] 5. Synthesis of compound e

[0624] To a stirred solution of N-(6-chloropyridin-3-yl)-N-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (400 mg, 1.4 mmol) and potassium tert-butoxide (469.6 mg, 4.2 mmol) in N,N-dimethylformamide (4 mL), iodomethane (594.1 mg, 4.2 mmol) was added fractionally under air at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The residue was purified by reversed-phase rapid chromatography to give N-(6-chloropyridin-3-yl)-N,1-dimethylpyrrolo[3,2-b]pyridine-3-carboxamide (160 mg, 38.13% yield). LCMS (ESI, m / z): [M+H] + =301.25

[0625] 6. Synthesis of Compound 76-1

[0626] To a stirred solution of N-(6-chloropyridin-3-yl)-N,1-dimethylpyrrolo[3,2-b]pyridine-3-carboxamide (100 mg, 0.3 mmol) and (1S,3S)-N1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclopentane-1,3-diamine (81 mg, 0.3 mmol) in tetrahydrofuran (1 mL), sodium tert-butoxy (128 mg, 1 mmol) and t-BuXPhos Pd G3 (26 mg, 0.03 mmol) were added fractionally at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 2 hours. The mixture was then concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography to obtain N-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-N,1-dimethylpyrrolo[3,2-b]pyridine-3-carboxamide (11.1 mg).

[0627] LCMS(ESI,m / z):[M+H] + =509.40

[0628] 1 H NMR(400MHz, Methanol-d4)δ8.33(d,J=4.7Hz,1H),8.17(s,2H),7.87–7.75 (m,2H),7.55(s,1H),7.45–7.37(m,1H),7.28–7.15(m,1H),6.70–6.55(m,1 H),6.39(d,J=9.0Hz,1H),4.33(p,J=6.7Hz,1H),4.25–4.10(m,1H),3.81(s ,3H),3.46(s,3H),2.26–2.13(m,2H),1.96–1.81(m,2H),1.62–1.44(m,2H).

[0629] Example 64

[0630] 1. Synthesis of compound a

[0631] To a stirred solution of methyl 1H-pyrrolo[3,2-b]pyridine-3-carboxylate (3 g, 17.0 mmol), a solution of potassium carbonate (5.9 g, 42.6 mmol) in DMF (40 mL) was added fractionally at room temperature under air. The resulting mixture was stirred for 30 minutes at room temperature. To the mixture, 1-(chloromethyl)-4-methoxybenzene (3.2 g, 20.4 mmol) was added fractionally at room temperature. The resulting mixture was stirred overnight at room temperature. The desired product was detected by LCMS. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (1:1) to give methyl 1-[(4-methoxyphenyl)methyl]pyrrolo[3,2-b]pyridine-3-carboxylate (3 g). LCMS (ESI, m / z): [M+H] + =297.30

[0632] 2. Synthesis of compound b

[0633] At room temperature, a solution of potassium hydroxide (2044.8 mg, 36.4 mmol) stirred in methanol (20 mL) and water (20 mL) was added in portions to methyl 1-[(4-methoxyphenyl)methyl]pyrrolo[3,2-b]pyridine-3-carboxylic acid (3.6 g, 12.1 mmol). The resulting mixture was stirred at room temperature for 2 hours. The desired product was detected by liquid chromatography-mass spectrometry. The resulting mixture was concentrated under reduced pressure to give 1-[(4-methoxyphenyl)methyl]pyrrolo[3,2-b]pyridine-3-carboxylic acid (2.4 g). LCMS (ESI, m / z): [M+H] + =283.05.

[0634] 3. Synthesis of compound c

[0635] To a stirred solution of 1-[(4-methoxyphenyl)methyl]pyrrolo[3,2-b]pyridine-3-carboxylic acid (2.4 g, 8.5 mmol) and 6-chloropyridine-3-amine (1.1 g, 8.5 mmol) in dichloromethane (30 mL), EDCI (2.0 g, 12.8 mmol) was added fractionally at room temperature under air. The resulting mixture was stirred for 2 hours at room temperature. The mixture was then concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography to give a white solid, N-(6-chloropyridin-3-yl)-1-[(4-methoxyphenyl)methyl]pyrrolo[3,2-b]pyridine-3-carboxamide (2.02 g). LCMS (ESI, m / z): [M+H] + =393.20.

[0636] 4. Synthesis of compound d

[0637] NaH (0.15 g, 6.1 mmol) was added in portions to a 20 mL solution of N-(6-chloropyridin-3-yl)-1-[(4-methoxyphenyl)methyl]pyrrolo[3,2-b]pyridine-3-carboxamide (2 g, 5.1 mmol) stirred at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for another 30 minutes. MeI (2.2 g, 15.3 mmol) was added dropwise to the mixture at 0 °C over a period of 1 minute. The resulting mixture was stirred at room temperature for another hour. The reaction was quenched with ice water at 0 °C. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography to give N-(6-chloropyridin-3-yl)-1-[(4-methoxyphenyl)methyl]-N-methylpyrrolo[3,2-b]pyridine-3-carboxamide (1.6 g) as a white solid. LCMS (ESI, m / z): [M+H] + =407.20

[0638] 5. Synthesis of Compound 76-2

[0639] Under a nitrogen atmosphere, at room temperature, t-BuXPhos Pd G3 (19.5 mg, 0.02 mmol) and t-BuONa (94.5 mg, 1.0 mmol) were added in portions to a solution of N-(6-chloropyridin-3-yl)-1-[(4-methoxyphenyl)methyl]-N-methylpyrrolo[3,2-b]pyridine-3-carboxamide (100 mg, 0.2 mmol) and (1S,3S)-N1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclopentane-1,3-diamine (60.0 mg, 0.2 mmol) stirred in tetrahydrofuran (1 mL). The resulting mixture was stirred at 90 °C for 2 hours. The mixture was filtered, and the filter cake was washed with acetonitrile. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography to give N-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-[(4-methoxyphenyl)methyl]-N-methylpyrrolo[3,2-b]pyridine-3-carboxamide (13.7 mg).

[0640] LCMS(ESI,m / z):[M+H] + =615.35

[0641] 1H NMR (400MHz, Methanol-d4) δ8.35(d,J=4.4Hz,1H),8.17(d,J=8.4Hz,2H),7.78(d,J=7.9 Hz,2H),7.48(s,1H),7.36(d,J=8.9Hz,1H),7.21–7.10(m,1H),6.96(d,J=8.1Hz,2H),6. 90–6.52(m,3H),6.40(d,J=8.9Hz,1H),5.26(s,2H),4.38–4.28(m,1H),4.17(t,J=6.5Hz ,1H),3.75(s,3H),3.45(s,3H),2.25–2.15(m,2H),1.98–1.84(m,2H),1.61–1.46(m,2H).

[0642] Example 65

[0643] 1. Synthesis of compound 80-4

[0644] To a solution of (6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)acetic acid (100 mg, 0.2 mmol) and 7H-pyrrol[2,3-c]pyridine (31 mg, 0.2 mmol) in dichloromethane (1 mL), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (150 mg, 0.3 mmol) and N,N-diisopropylethylamine (102 mg, 0.7 mmol) were added. The resulting mixture was stirred at room temperature in air for 2 hours. The mixture was then concentrated under reduced pressure. The 2-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-{pyrrolidone[2,3-c]pyridin-7-yl}ethanetanone (12.8 mg, yield 10.11%) was purified by flash chromatography.

[0645] LCMS(ESI,m / z): [M+H] + =430.30

[0646] 1H NMR(400MHz,DMSO-d6)δ9.15(d,J=5.3Hz,1H),8.32(d,J=4.0Hz,1H),8.23(s,2H ),8.02(d,J=5.4Hz,1H),7.96(d,J=2.4Hz,1H),7.46(d,J=7.2Hz,1H),7.45–7.32 (m,1H),7.24–6.77(m,2H),6.52(d,J=6.9Hz,1H),6.45(d,J=8.6Hz,1H),4.82(s, 2H),4.29–4.16(m,2H),2.11–2.01(m,2H),1.93–1.81(m,2H),1.56–1.42(m,2H).

[0647] Example 66

[0648] 1. Synthesis of compound 80-5

[0649] To a solution of (6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)acetic acid (100 mg, 0.2 mmol) and H-pyrrolo[2,3-D]pyrimidine (31 mg, 0.2 mmol) in dichloromethane (1 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (122 mg, 0.7 mmol) and 4-dimethylaminopyridine (3 mg, 0.02 mmol) were added. The resulting mixture was stirred at room temperature in air for 2 hours. The mixture was then concentrated under reduced pressure. The product was purified by flash chromatography to obtain 2-(6-{(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-{pyron[2,3-d]pyrimidin-7-yl}ethanetanone (19.4 mg, yield 15.32%).

[0650] LCMS(ESI,m / z): [M+H] + =481.25

[0651] 1H NMR(400MHz, DMSO-d6)δ9.11(d,J=33.7Hz,2H),8.23(s,2H),8.06(d,J=4.0 Hz,1H),7.94(d,J=2.3Hz,1H),7.46(d,J=7.2Hz,1H),7.41–7.32(m,1H),7. 24–6.80(m,2H),6.56(d,J=6.9Hz,1H),6.46(d,J=8.5Hz,1H),4.69(s,2H), 4.28–4.20(m,2H),2.18–2.08(m,2H),1.92–1.80(m,2H),1.49–1.41(m,2H).

[0652] Example 67

[0653] 1. Synthesis of compound a

[0654] A solution of 5-bromo-1H-pyrazolo[3,4-b]pyridine (5.0 g, 25.2 mmol) in N,N-dimethylformamide (50 mL) was stirred at 0 °C in air for 2 minutes. Sodium cyanide (1.2 g, 50.5 mmol) was added to the mixture in portions over 10 minutes at 0 °C. The resulting mixture was stirred at 0 °C for another 30 minutes. 4-Methoxybenzyl chloride (4.7 g, 30.3 mmol) was added dropwise to the mixture at 0 °C. The resulting mixture was stirred overnight at room temperature. The reaction was terminated by adding ice water (20 mL) at 0 °C. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (2:1) to give 5-bromo-1-[(4-methoxyphenyl)methyl]pyrazolo[3,4-b]pyridine (5.2 g, 64.73% yield) as an orange solid. LCMS (ESI, m / z): [M+H] + =318.10.

[0655] 2. Synthesis of compound b

[0656] A solution of 5-bromo-1-[(4-methoxyphenyl)methyl]pyrazolo[3,4-b]pyridine (3.1 g, 9.7 mmol), palladium acetate (0.8 g, 3.8 mmol), N,N,N',N'-tetramethylethylenediamine (4.5 g, 38.9 mmol), and di(1-adamantyl)-N-butylphosphine (1.4 g, 3.8 mmol) in toluene (35 mL) was stirred for 2 days at 105 °C under a carbon monoxide and hydrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure after filtration. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (1:1), to give 1-[(4-methoxyphenyl)methyl]pyrazolo[3,4-b]pyridine-5-carboxaldehyde (1.5 g, 57.60% yield) as a brown solid. LCMS(ESI,m / z): [M+H] + =268.10.

[0657] 3. Synthesis of compound c

[0658] A solution of 1-[(4-methoxyphenyl)methyl]pyrazolo[3,4-b]pyridine-5-carboxaldehyde (1.0 g, 3.7 mmol) in dichloromethane (10 mL) was stirred for 2 minutes at room temperature in air. Diisopropylaminothiophosphate (1.2 g, 7.4 mmol) was added dropwise to the mixture at room temperature. The resulting mixture was stirred overnight at room temperature. The reaction was terminated by adding 20 mL of saturated sodium bicarbonate solution at room temperature. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (1:1), to give 5-(difluoromethyl)-1-[(4-methoxyphenyl)methyl]pyrazolo[3,4-b]pyridine (330 mg, 30.49% yield) as a white solid. LCMS (ESI, m / z): [M+H] + =290.10.

[0659] 4. Synthesis of compound d

[0660] A solution of 5-(difluoromethyl)-1-[(4-methoxyphenyl)methyl]pyrazolo[3,4-b]pyridine (800 mg, 2.7 mmol) in 10 mL of trifluoroacetic acid was stirred overnight at 60 °C in air. The mixture was cooled to room temperature. The mixture / residue was alkalized to pH 8 with triethylamine. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure after filtration. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (2:1) to give 5-(difluoromethyl)-1H-pyrazolo[3,4-b]pyridine (400 mg, 85.52% yield) as a white solid. LCMS (ESI, m / z): [M+H] + =170.10.

[0661] 5. Synthesis of compound 80-7

[0662] A solution of (6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)acetic acid (100 mg, 0.2 mmol), 5-(difluoromethyl)-1H-pyrazolo[3,4-b]pyridine (44 mg, 0.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (122 mg, 0.7 mmol), and 4-dimethylaminopyridine (3 mg, 0.02 mmol) in dichloromethane (1 mL) was stirred in air at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. Column: DAICEL DCpak P4VP 3*25 cm, 5 μm; Mobile phase A: CO2, Mobile phase B: acetonitrile; Flow rate: 90 mL / min; Gradient (B%): Isocratic 45% B; Column temperature (°C): 35; Back pressure (bar): 100; Wavelength: 254 nm; RT1 (min): 4.37; Total elution time (min): 8; Injection volume: 0.5 mL; Number of runs: 3, yielding 2-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-[5-(difluoromethyl)pyrazolo[3,4-b]pyridin-1-yl]acetone (11.7 mg, 8.37% yield).

[0663] LCMS(ESI,m / z):[M+H] + =531.30

[0664] 1H NMR(400MHz, DMSO-d6)δ8.96(m,1H),8.66(d,J=3.7Hz,2H),8.23(s,2H),7.95(d,J=2.3Hz,1H),7.52–7.21(m,3H),7.20–6.79(m,1H), 6.52(d,J=6.9Hz,1H),6.45(d,J=8.6Hz,1H),4.45(s,2H),4.28–4.15(m,2H),2.18–2.04(m,2H),1.86–1.71(m,2H),1.58–1.42(m,2H).

[0665] Example 68

[0666] 1. Synthesis of Compound 82

[0667] To a solution of (100 mg, 0.2 mmol) acetic acid and 2H-indazole (31 mg, 0.2 mmol) in dichloromethane (1 mL) at room temperature and air, N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (150 mg, 0.3 mmol) and N,N-diisopropylethylamine (102 mg, 0.7 mmol) were added. The resulting mixture was stirred overnight at room temperature under air. The mixture was then concentrated under reduced pressure. 2-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-(indazol-2-yl) acetone (10.2 mg, yield 8.07%) was purified by flash chromatography.

[0668] LCMS(ESI,m / z): [M+H] + =480.20

[0669] 1H NMR(400MHz,DMSO-d6)δ8.54(s,1H),8.36–8.25(m,1H),8.23(s,2H),7.98–7.94 (m,1H),7.92(d,J=1.0Hz,1H),7.64–7.61(m,1H),7.48–7.44(m,2H),7.42–7.36( m,1H),7.13–7.03(m,1H),6.52(d,J=6.9Hz,1H),6.45(d,J=8.5Hz,1H),4.35(s, 2H),4.28–4.20(m,2H),2.10–2.01(m,2H),1.92–1.79(m,2H),1.49–1.30(m,2H).

[0670] Example 69

[0671] 1. Synthesis of Compound 89

[0672] Manganese dioxide (881.8 mg, 10.1 mmol) was aliquoted into a 5 mL solution of 1-(2,5-dihydropyridin-1-yl)-2-(6-{(1S,3S)-3-[(5-methyl-1,2,4-thiadiazol-3-yl)amino]cyclopentyl]aminopyridin-3-yl)acetone (130 mg, 0.3 mmol) in DCM. The resulting mixture was stirred overnight at 50 °C in air. The mixture was then concentrated under reduced pressure. The crude product was purified by Prep-HPLC to give 2-(6-{(1S,3S)-3-[(5-methyl-1,2,4-thiadiazol-3-yl)amino]cyclopentyl]amino}pyridin-3-yl)-1-(pyronin-1-yl)acetone (1.4 mg).

[0673] LCMS(ESI,m / z):[M+H] + =383.20

[0674] 1 H NMR(400MHz,Chloroform-d)δ7.87(s,1H),7.56–7.47(m,1H),7.37(s,2H),6.73(s,1H),6.51(d,J=8.8Hz,1H),6.34(t,J=2.4Hz,2H),5.3 5–5.16(m,1H),4.41–4.30(m,1H),4.19–4.09(m,1H),4.02(s,2H),2.67(s,3H),2.40–2.24(m,2H),2.17–2.01(m,2H),1.73–1.58(m,2H).

[0675] Example 70

[0676] 1. Synthesis of compound 89-1

[0677] 3-Bromo-5-methyl-1,2,4-thiadiazole (40 mg, 0.2 mmol) and 2-(6-{(1S,3S)-3-aminocyclopentyl]aminopyridin-3-yl)-1-(2,5-dihydropyridin-1-yl)acetone (63.9 mg, 0.2 mmol) were stirred thoroughly in THF (1 ml). Then, GPhos Pd G6 TES (21.1 mg, 0.1 mmol) and sodium trimethylsilicate (100 mg, 0.8 mmol) were added in portions under a nitrogen atmosphere at room temperature. The resulting mixture was stirred overnight at 50 °C under a nitrogen atmosphere. The mixture was then concentrated under reduced pressure. The crude product was purified by Prep-HPLC to obtain 1-(2,5-dihydropyridin-1-yl)-2-(6-{(1S,3S)-3-[(5-methyl-1,2,4-thiadiazol-3-yl)amino]cyclopentyl]aminopyridin-3-yl) acetone (9.8 mg).

[0678] LCMS(ESI,m / z):[M+H] + =385.20

[0679] 1 H NMR (400MHz, DMSO-d6) δ7.80(d,J=2.2Hz,1H),7.34(d,J=7.0Hz,1H),7.24(dd,J=8.6,2.4Hz,1H),6.41(dd,J=7.8,5.6Hz,2H),5.90(s,2H),4.31(d d,J=5.2,2.8Hz,2H),4.25–4.13(m,2H),4.06(t,J=4.0Hz,2H),3.43(s,2 H),2.62(s,3H),2.14–2.04(m,2H),1.94–1.77(m,2H),1.57–1.38(m,2H).

[0680] Example 71

[0681] 1. Synthesis of Compound 92

[0682] At room temperature and in an air atmosphere, MnO2 (562.2 mg, 6.5 mmol) was aliquoted into a stirred solution of 1-(2,5-dihydropyridine-1-yl)-2-(6-{(1S,3S)-3-({6-methyl-[1,2,4]triazol[1,5-a]pyridin-2-yl}amino)cyclopentyl]aminopyridin-3-yl)acetone (90 mg, 0.2 mmol) in DCM (2 mL). The resulting mixture was stirred overnight in air at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography to give 2-(6-{(1S,3S)-3-({6-methyl-[1,2,4]triazol[1,5-a]pyridin-2-yl}amino)cyclopentyl]aminopyridin-3-yl)-1-(pyridin-1-yl)acetone (1.2 mg).

[0683] LCMS(ESI,m / z):[M+H] + =416.20

[0684] 1 H NMR(400MHz,Chloroform-d)δ8.14(s,1H),7.95(d,J=2.4Hz,1H),7.47(dd,J=8.8,2.4Hz, 1H),7.37(t,J=2.4Hz,2H),7.30(d,J=8.8Hz,1H),7.22(dd,J=9.0,1.8Hz,1H),6.47(d,J= 8.6Hz,1H),6.33(t,J=2.4Hz,2H),5.34(s,1H),4.45(d,J=6.8Hz,1H),4.39–4.29(m,1H), 4.27–4.17(m,1H),4.02(s,2H),2.42–2.30(m,5H),2.19–2.03(m,2H),1.71–1.56(m,2H).

[0685] Example 72

[0686] 1. Synthesis of compound 92-1

[0687] To a solution of 1-(2,5-dihydropyrrolo-1-yl)-2-(6-{[(1S,3S)-3-({7-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl}amino)cyclopentyl]amino}pyridin-3-yl)acetone (400 mg, 0.9 mmol) in 6 mL of 1,2-dichloroethane, manganese dioxide (2.5 g, 28.7 mmol) was added in portions under air at room temperature. The resulting mixture was stirred overnight at 60 °C. The mixture was filtered, and the filter cake was washed with methyl cyanide. The filtrate was concentrated under reduced pressure. The crude product (mg) was purified by preparative high performance liquid chromatography to give 2-(6-{[(1S,3S)-3-({7-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl}amino)cyclopentyl]amino}pyridin-3-yl)-1-(pyrrolo-1-yl)acetone (12.0 mg, 3.01% yield).

[0688] LCMS(ESI,m / z): [M+H] + =416.20

[0689] 1 H NMR(400MHz,Methanol-d4)δ8.29(d,J=6.8Hz,1H),7.89(d,J=2.4Hz,1H),7.50– 7.46(m,2H),7.41(dd,J=8.7,2.4Hz,1H),7.20–7.18(m,1H),6.80(dd,J=6.9,1.8 Hz,1H),6.55(d,J=8.4Hz,1H),6.36–6.29(m,2H),4.32–4.21(m,2H),4.12(s,2H) ,2.44(d,J=0.9Hz,3H),2.35–2.24(m,2H),2.12–1.97(m,2H),1.74–1.55(m,2H).

[0690] Example 73

[0691] 1. Synthesis of compound a

[0692] Under ambient air at room temperature, a solution of t-BuONO (6.9 g, 67.5 mmol) and CuBr2 (4.5 g, 20.2 mmol) in 20 mL of ACN was stirred, and 7-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-amine (2 g, 13.5 mmol) was added in portions. The resulting mixture was stirred at 60 °C for 30 min. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:1) to give 2-bromo-7-methyl-[1,2,4]triazolo[1,5-a]pyridine (2 g, 69.87% yield) as a white solid.

[0693] LCMS(ESI,m / z): [M+H] + =212.05

[0694] 2. Synthesis of compound 92-10

[0695] To a stirred solution of 2-bromo-7-methyl-[1,2,4]triazolo[1,5-a]pyridine (100 mg, 0.5 mmol) and 2-(6-{[(1S,3S)-3-aminocyclopentyl]amino}pyridin-3-yl)-1-(2,5-dihydropyrrolo-1-yl)acetone (135.1 mg, 0.5 mmol) in tetrahydrofuran (1 mL), GPhos Pd G6 TES (44.5 mg, 0.05 mmol) and TMSONa (211.6 mg, 1.9 mmol) were added fractionally at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 50 °C for 2 hours. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions to obtain 1-(2,5-dihydropyrrolo-1-yl)-2-(6-{[(1S,3S)-3-({7-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl}amino)cyclopentyl]amino}pyridin-3-yl)acetone (14.1 mg).

[0696] LCMS(ESI,m / z): [M+H] + =418.25

[0697] 1H NMR (400MHz, Methanol-d4) δ8.29(d,J=6.8Hz,1H),7.84(d,J=2.2Hz,1H),7.39(dd,J =8.7,2.4Hz,1H),7.19–7.14(m,1H),6.80(dd,J=6.9,1.9Hz,1H),6.54(d,J=8.6Hz,1H ),5.93–5.89(m,2H),4.40–4.37(m,2H),4.33–4.22(m,2H),4.23–4.19(m,2H),3.56(s ,2H),2.44(d,J=1.6Hz,3H),2.32–2.24(m,2H),2.13–1.95(m,2H),1.73–1.54(m,2H).

[0698] Example 74

[0699] 1. Synthesis of Compound 92-11

[0700] 2-Bromo-6-methyl-[1,2,4]triazol[1,5-a]pyridine (100 mg, 0.4 mmol) and 2-(6-{(1S,3S)-3-aminocyclopentyl]amino}pyridin-3-yl)-1-(2,5-dihydropyrrolo-1-yl)acetone (135 mg, 0.4 mmol) were stirred in THF (2 mL), and then GPhos Pd G6 TES (44.5 mg, 0.04 mmol) and sodium trimethylsilicate (211.6 mg, 1.9 mmol) were added aliquots under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 50 °C under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography to obtain 1-(2,5-dihydropyrrolo-1-yl)-2-(6-((1S,3S)-3-((6-methyl-[1,2,4]triazol[1,5-a]pyridin-2-yl)amino)cyclopentyl)aminopyridin-3-yl)ethylenedione (11.1 mg).

[0701] LCMS(ESI,m / z):[M+H] + =418.30

[0702] 1H NMR (400MHz, DMSO-d6) δ8.42(s,1H),7.80(s,1H),7.31–7.19(m,3H),6.49(d,J=7.2Hz,1H),6.45–6.35(m,2H),5.90(s,2H) ,4.32–4.22(m,3H),4.18–4.01(m,3H),3.43(s,2H),2.27(s,3H),2.17–2.06(m,2H),1.97–1.78(m,2H),1.61–1.38(m,2H).

[0703] Example 75

[0704] 1. Synthesis of Compounds 92-12

[0705] Palladium (5 mg, 0.05 mmol) was added in portions to a methanol (1 mL) solution of 1-(2,5-dihydropyrrolo-1-yl)-2-(6-{[(1S,3S)-3-({7-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl}amino)cyclopentyl]amino}pyridin-3-yl)acetone (50 mg, 0.1 mmol) at room temperature under a hydrogen atmosphere. The resulting mixture was stirred overnight at room temperature. The mixture was filtered, and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure. The crude product (mg) was purified by preparative high performance liquid chromatography to obtain 2-(6-{[(1S,3S)-3-({7-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl}amino)cyclopentyl]amino}pyridin-3-yl)-1-(pyrrolidine-1-yl)acetone (12.5 mg).

[0706] LCMS(ESI,m / z): [M+H] + =420.25

[0707] 1 H NMR (400MHz, Methanol-d4) δ8.29(d,J=6.9Hz,1H),7.82(d,J=2.3Hz,1H),7.39(dd,J=8.7,2.4Hz,1H),7.19–7.16(m,1H),6.81(dd,J=6.9,1.8Hz,1H),6 .55(d,J=8.7Hz,1H),4.31–4.21(m,2H),3.60–3.53(m,4H),3.44(t,J=6.9Hz ,2H),2.44(s,3H),2.33–2.24(m,2H),2.08–1.87(m,6H),1.74–1.55(m,2H).

[0708] Example 76

[0709] 1. Synthesis of compound a

[0710] Under ambient air at room temperature, a solution of t-BuONO (6.9 g, 67.5 mmol) and CuBr2 (4.5 g, 20.2 mmol) in 20 mL of ACN was stirred, and 7-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-amine (2 g, 13.5 mmol) was added in portions. The resulting mixture was stirred at 60 °C for 30 min. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:1) to give 2-bromo-7-methyl-[1,2,4]triazolo[1,5-a]pyridine (2 g, 69.87% yield) as a white solid.

[0711] LCMS(ESI,m / z): [M+H] + =212.05

[0712] 2. Synthesis of Compound 92-21

[0713] To a stirred solution of 2-bromo-7-methyl-[1,2,4]triazolo[1,5-a]pyridine (100 mg, 0.5 mmol) and N-(6-{[(1S,3S)-3-aminocyclopentyl]amino}pyridin-3-yl)-N,1-dimethylimidazol-4-carboxamide (148.3 mg, 0.5 mmol) in tetrahydrofuran (2 mL), GPhos Pd G6 TES (44.5 mg, 0.05 mmol) and TMSONa (211.6 mg, 1.9 mmol) were added fractionally at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 2 hours at room temperature. The mixture was filtered, and the filter cake was washed with acetonitrile. The filtrate was concentrated under reduced pressure. The crude product (mg) was purified by preparative high performance liquid chromatography to obtain N,1-dimethyl-N-(6-{[(1S,3S)-3-({7-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl}amino)cyclopentyl]amino}pyridin-3-yl)imidazol-4-carboxamide (10.2 mg).

[0714] LCMS(ESI,m / z): [M+H] + =446.25

[0715] 1H NMR(400MHz,DMSO-d6)δ8.43(d,J=6.8Hz,1H),7.72(s,1H),7.43(s,1H),7.23 (dd,J=8.7,2.7Hz,1H),7.16(s,1H),6.69(dd,J=6.8,1.8Hz,1H),6.60(d,J=6. 9Hz,1H),6.50(d,J=7.3Hz,1H),6.42(d,J=8.8Hz,1H),4.26–4.11(m,2H),3.57 (s,3H),2.35(s,3H),2.16–2.08(m,2H),1.95–1.80(m,2H),1.59–1.42(m,2H).

[0716] Example 77

[0717] 1. Synthesis of compound a

[0718] To a stirred mixture of 7-bromo-[1,2,4]triazolo[1,5-a]pyridine (6.0 g, 30.3 mmol) and N,N,N',N'-tetramethylethylenediamine (14.0 g, 121.2 mmol) in toluene (80 mL), di(1-adamantyl)-N-butylphosphine (4.3 g, 12.1 mmol) and Pd(OAc)₂ (2.7 g, 12.1 mmol) were added. The resulting mixture was stirred at 105 °C under a hydrogen / carbon monoxide atmosphere of 40 atm for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH₂Cl₂ / MeOH (0–10%), to give [1,2,4]triazolo[1,5-a]pyridine-7-carboxaldehyde (4.1 g) as a yellow oil.

[0719] LCMS(ESI,m / z):[M+H] + =148.03

[0720] 2. Synthesis of compound b

[0721] Under a nitrogen atmosphere, diethylamine trifluoride (5.3 g, 33.4 mmol) was added dropwise to a solution of [1,2,4]triazolo[1,5-a]pyridine-7-carboxaldehyde (4.1 g, 27.8 mmol) in dichloromethane (50 mL) at 0 °C. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was quenched with ice water at room temperature. The resulting mixture was extracted with dichloromethane. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (0-50%), to give 7-(difluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine (1.2 g) as a white solid.

[0722] LCMS(ESI,m / z):[M+H] + =170.04

[0723] 3. Synthesis of compound c

[0724] Under a nitrogen atmosphere, n-butyllithium (0.4 g, 7.0 mmol) was added dropwise to a stirred solution of 7-(difluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine (1.2 g, 7.1 mmol) tetrahydrofuran (15 mL) at -78 °C. The resulting mixture was stirred at -78 °C for 1 hour under a nitrogen atmosphere. 1,3-Dibromo-1,1,3,3-tetrafluoropropane (1.9 g, 7.1 mmol) was added to the mixture at -78 °C. The resulting mixture was stirred at -78 °C for another 1 hour. The reaction was quenched with a saturated aqueous solution of ammonium chloride at room temperature. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with petroleum ether / ethyl acetate (0-50%) to give a white solid 2-bromo-7-(difluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine (700 mg).

[0725] LCMS(ESI,m / z):[M+H] + =248.03

[0726] 4. Synthesis of compound d

[0727] To a mixture of 2-bromo-7-(difluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine (400 mg, 1.6 mmol) and 2-(6-{[(1S,3S)-3-aminocyclopentyl]amino}pyridin-3-yl)-1-(2,5-dihydropyrrolo-1-yl)acetone (461 mg, 1.6 mmol) dioxane (5 mL), (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylylene]dichloro(2-methylpyridine)palladium (135 mg, 0.1 mmol) and cesium carbonate (1.5 g, 4.8 mmol) were added. The resulting mixture was stirred at 80 °C for 2 hours under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with petroleum ether / ethyl acetate (0-80%) to give 2-(6-{[(1S,3S)-3-{[7-(difluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-(2,5-dihydropyrrole-1-yl)acetone (220 mg), a yellow oil.

[0728] LCMS(ESI,m / z):[M+H] + =454.50

[0729] 5. Synthesis of Compound 93-1

[0730] 2-(6-{[(1S,3S)-3-{[7-(difluoromethyl))-[1,2,4]triazol[1,5-A]pyridin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-(2,5-dihydropyridin-1-yl)acetone (200 mg, 0.4 mmol) and MnO2 (383 mg, 4.4 mmol) were stirred in 1,2-dichloroethane solution (5 mL) for 3 days. The resulting mixture was filtered, and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography to obtain 2-(6-{(1S,3S)-3-{[7-(difluoromethyl)-[1,2,4]triazol[1,5-a]pyridin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-(pyridin-1-yl)acetone (4.0 mg).

[0731] LCMS(ESI,m / z):[M+H] + =452.35

[0732] 1H NMR (400MHz, Methanol-d4) δ8.42 (s, 1H), 7.91 (d, J = 2.4Hz, 1H), 7.51–7.46 (m, 2H), 7. 43(dd,J=8.8,2.4Hz,1H),7.18(d,J=1.6Hz,1H),7.04–6.70(m,1H),6.58(d,J=8.8Hz,1 H),6.39–6.35(m,1H),6.33(t,J=2.4Hz,2H),4.44–4.26(m,2H),4.14(s,2H),2.52–2. 40(m,1H),2.39–2.23(m,2H),2.14–2.04(m,1H),1.94–1.77(m,1H),1.76–1.63(m,1H).

[0733] Example 78

[0734] 1. Synthesis of compound a

[0735] A solution of 2-(6-{[(1S,3S)-3-aminocyclopentyl]amino}pyridin-3-yl)-1-(2,5-dihydropyrrolo-1-yl)acetone (500 mg, 1.7 mmol) and diisopropylethylamine (451 mg, 3.4 mmol) in tetrahydrofuran (8 mL) was added with cyanogen bromide (184 mg, 1.7 mmol). The resulting mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (0-80%), to give {(1S,3S)-3-({5-[2-(2,5-dihydropyrrolo-1-yl)-2-oxoethyl]pyridin-2-yl}amino)cyclopentyl]amino}formonitrile (380 mg), as a yellow oil.

[0736] LCMS(ESI,m / z):[M+H] + =312.17

[0737] 2. Synthesis of compound b

[0738] Hydroxylamine hydrochloride (101 mg, 1.4 mmol) was added to a mixture of (1S,3S)-3-({5-[2-(2,5-dihydropyrrolo-1-yl)-2-oxoethyl]pyridin-2-yl}amino)cyclopentylcarbamate (380 mg, 1.2 mmol) and triethylamine (246 mg, 2.4 mmol) in ethanol (5 mL). The resulting mixture was stirred overnight at 50 °C. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with dichloromethane / methanol (0-15%), to give N-[(1S,3S)-3-({5-[2-(2,5-dihydropyrrolo-1-yl)-2-oxoethyl]pyridin-2-yl}amino)cyclopentyl]-N'-hydroxyguanidine (240 mg) as a white solid.

[0739] LCMS(ESI,m / z):[M+H] + =345.20

[0740] 3. Synthesis of compound c

[0741] A solution of N-[(1S,3S)-3-({5-[2-(2,5-dihydropyrrolo-1-yl)-2-oxoethyl]pyridin-2-yl}amino)cyclopentyl]-N'-hydroxyguanidine (240 mg, 0.7 mmol) in trichloroacetic anhydride (2 mL) was stirred at 60 °C for 1 hour. The resulting mixture was extracted with dichloromethane. The combined organic layers were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give a yellow crude oil, 1-(2,5-dihydropyrrolo-1-yl)-2-(6-{[(1S,3S)-3-{[5-(trichloromethyl)-1,2,4-oxadiazol-3-yl]amino}cyclopentyl]amino}pyridin-3-yl)acetone (170 mg). The crude product was used directly in the next reaction without further purification.

[0742] LCMS(ESI,m / z):[M+H] + =471.08

[0743] 4. Synthesis of compound d

[0744] A solution of 1-(2,5-dihydropyrrolo-1-yl)-2-(6-{[(1S,3S)-3-{[5-(trichloromethyl)-1,2,4-oxadiazol-3-yl]amino}cyclopentyl]amino}pyridin-3-yl)acetone (170 mg, 0.360 mmol) was placed in a methanol solution of methylamine (31%, 3 mL) and stirred at 60 °C for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with dichloromethane / methanol (0-10%), to give 1-(2,5-dihydropyrrolo-1-yl)-2-(6-{[(1S,3S)-3-{[5-(methylamino)-1,2,4-oxadiazol-3-yl]amino}cyclopentyl]amino}pyridin-3-yl)acetone (47 mg), a white solid.

[0745] LCMS(ESI,m / z):[M+H] + =384.21

[0746] 5. Synthesis of Compound 97

[0747] A solution of 1-(2,5-dihydropyridin-1-yl)-2-(6-{[(1S,3S)-3-{[5-(methylamino)-1,2,4-oxadiazol-3-yl]amino}cyclopentyl]amino}pyridin-3-yl) acetone (40 mg, 0.1 mmol) and manganese dioxide (90 mg, 1.0 mmol) in 1,2-dichloroethane (1 mL) was stirred at room temperature for 2 days. The resulting mixture was filtered, and the filter cake was washed with dichloromethane. The filtrate was concentrated under reduced pressure. Purification was performed by preparative high-performance liquid chromatography to give 2-(6-{[(1S,3S)-3-{[5-(methylamino)-1,2,4-oxadiazol-3-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-(pyron-1-yl) acetone (0.6 mg).

[0748] LCMS(ESI,m / z):[M+H] + =382.30

[0749] 1 H NMR (400MHz, Methanol-d4) δ7.88(d,J=2.4Hz,1H),7.51–7.45(m,2H),7.40(dd,J=8.8,2.4Hz,1H),6.53(d,J=8.8Hz,1H),6.35–6.3 0(m,2H),4.28–4.20(m,1H),4.12(s,2H),3.98–3.88(m,1H),2.91(s,3H),2.27–2.15(m,2H),2.07–1.84(m,2H),1.66–1.48(m,2H).

[0750] Example 79

[0751] 1. Synthesis of compound a

[0752] To a stirred solution / mixture of 2-bromopyrimidin-4-amine (1 g, 5.7 mmol) and propionic acid (425.7 mg, 5.7 mmol) in dichloromethane (10 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.3 g, 8.6 mmol) and 4-dimethylaminopyridine (1.1 g, 8.6 mmol) were added fractionally under air at room temperature. The resulting mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water, gradient from 5% to 100% over 30 min; detector, UV 254 nm. The result was a white solid N-(2-bromopyrimidin-4-yl)propionamide (300 mg, 22.69% yield).

[0753] LCMS(ESI,m / z): [M+H] + =229.90

[0754] 2. Synthesis of compound b

[0755] Under a nitrogen atmosphere, diisopropylethylamine (505.6 mg, 3.9 mmol) was added fractionally to a solution of N-(2-bromopyrimidin-4-yl)propionamide (300 mg, 1.3 mmol) and tert-butyl N-[(1S,3S)-3-aminocyclopentyl]carbamate (261.2 mg, 1.3 mmol) in dimethyl sulfoxide (3 mL) at room temperature. The resulting mixture was stirred overnight at 110 °C. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile gradient in water from 5% to 100%, 30 min; detector, 254 nm UV. Tert-butyl N-[(1S,3S)-3-[(4-propionamidepyrimidin-2-yl)amino]cyclopentyl]carbamate (300 mg, yield 65.84%) was obtained as a white solid.

[0756] LCMS(ESI,m / z): [M+H] + =350.15

[0757] 3. Synthesis of compound c

[0758] Under ambient air and at room temperature, a 2 mL solution of 1,4-dioxane in 4.0 mol / L hydrochloric acid was added in portions to tert-butyl N-[(1S,3S)-3-[(4-propamidopyrimidin-2-yl)amino]cyclopentyl]carbamate (300 mg, 0.859 mmol). The resulting mixture was stirred for 2 hours at room temperature. The mixture was then concentrated under vacuum to give N-(2-{[(1S,3S)-3-aminocyclopentyl]amino}pyrimidin-4-yl)propionamide (300 mg, crude product) as a black solid.

[0759] LCMS(ESI,m / z): [M+H] + =250.30

[0760] 4. Synthesis of compound d

[0761] To a stirred solution of N-methylpyrrolidone (3 mL) containing N-(2-{[(1S,3S)-3-aminocyclopentyl]amino}pyrimidin-4-yl)propionamide (300 mg, 1.2 mmol) and 2-(6-chloropyridin-3-yl)-1-(2,5-dihydropyrrolidinyl-1-yl)acetone (267.9 mg, 1.2 mmol), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (95.6 mg, 0.1 mmol) and potassium tert-butoxide (540.1 mg, 4.8 mmol) was added fractionally at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 110 °C for 2 hours. The mixture was filtered, and the filter cake was washed with MeCN. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 5% to 100% gradient, 30 min; detector, UV 254 nm. N-(2-{[(1S,3S)-3-({5-[2-(2,5-dihydropyrrolo-1-yl)-2-oxoethyl]pyridin-2-yl}amino)cyclopentyl]amino}pyrimidin-4-yl)propionamide (97 mg, 18.51% yield) was given as a white solid.

[0762] LCMS(ESI,m / z): [M+H] + =436.35

[0763] 5. Synthesis of Compound 113

[0764] To a solution of N-(2-{[(1S,3S)-3-({5-[2-(2,5-dihydropyrrolo-1-yl)-2-oxoethyl]pyridin-2-yl}amino)cyclopentyl]amino}pyrimidin-4-yl)propionamide (50 mg, 0.1 mmol) in dichloromethane (2 mL), manganese dioxide (598.8 mg, 6.9 mmol) was added in portions under air at room temperature. The resulting mixture was stirred at 60 °C for 5 days. The mixture was filtered, and the filter cake was washed with dichloromethane. The filtrate was concentrated under reduced pressure. The crude product (mg) was purified by Prep-HPLC to give N-(2-{[(1S,3S)-3-({5-[2-oxo-2-(pyrrolo-1-yl)ethyl]pyridin-2-yl}amino)cyclopentyl]amino}pyrimidin-4-yl)propionamide (1.6 mg).

[0765] LCMS(ESI,m / z): [M+H] + =434.20

[0766] 1 H NMR (400MHz, Methanol-d4) δ8.11(s,1H),7.90(s,1H),7.48(t,J=2.4Hz,2H),7.42(d d,J=8.7,2.2Hz,1H),7.32(d,J=5.5Hz,1H),6.55(d,J=8.6Hz,1H),6.33(t,J=2.3Hz,2 H),4.60(s,1H),4.43–4.39(m,1H),4.28–4.23(m,1H),4.13(s,2H),2.45(q,J=7.5Hz ,2H),2.32–2.22(m,2H),2.05–1.93(m,2H),1.67–1.53(m,2H),1.18(t,J=7.5Hz,3H).

[0767] Example 80

[0768] 1. Synthesis of compound a

[0769] To a solution of ethyl 2-chloro-4-methylpyrimidin-5-carboxylate (500 mg, 2.4 mmol) and 2-(6-{[(1S,3S)-3-aminocyclopentyl]amino}pyridin-3-yl)-1-(2,5-dihydropyrrolo-1-yl)acetone (856 mg, 2.9 mmol) in DMSO (5 mg), potassium carbonate (1.0 g, 7.4 mmol), cuprous iodide (18 mg, 0.1 mmol), and N-(2,6-dimethylphenyl)-6-hydroxypyridine-2-carboxamide (36 mg, 0.15 mmol) were added. The resulting mixture was stirred at 110 °C for 2 hours under nitrogen. The residue was purified by reversed-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water (0.1% ammonia), 0%–50% gradient, 10 min; detector, UV 254 nm. The result was ethyl 2-{[(1S,3S)-3-({5-[2-(2,5-dihydropyrrolo-1-yl)-2-oxoethyl]pyridin-2-yl}amino]cyclopentyl}amino}-4-methylpyrimidin-5-carboxylate (400 mg), a yellow solid.

[0770] LCMS(ESI,m / z): [M+H] + =451.24

[0771] 2. Synthesis of compound b

[0772] A mixture of ethyl 2-{[(1S,3S)-3-({5-[2-(2,5-dihydropyrrolo-1-yl)-2-oxoethyl]pyridin-2-yl}amino)cyclopentyl}amino}-4-methylpyrimidin-5-carboxylate (300 mg, 0.6 mmol) in methylamine (33%, methanol) (3 mL) was stirred at 25 °C. The resulting mixture was stirred overnight at 80 °C under nitrogen. The desired product was detected by LC-MS. The residue was purified by reversed-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water (0.1% ammonia), 30%–90% gradient, 10 min; detector, UV 254 nm. The result was 2-{[(1S,3S)-3-({5-[2-(2,5-dihydropyrrolo-1-yl)-2-oxoethyl]pyridin-2-yl}amino)cyclopentyl]amino}-N,4-dimethylpyrimidin-5-carboxamide (50 mg), which was a yellow solid.

[0773] LCMS(ESI,m / z): [M+H] + =436.24

[0774] 3. Synthesis of Compound 114-2

[0775] MnO2 (29 mg, 0.3 mmol) was added to a solution of 2-{[(1S,3S)-3-({5-[2-(2,5-dihydropyrrolo-1-yl)-2-oxoethyl]pyridin-2-yl}amino)cyclopentyl}amino}-N,4-dimethylpyrimidine-5-carboxamide (30 mg, 0.07 mmol) in 1 mL of 1,2-dichloroethane under air atmosphere. The resulting mixture was stirred in air at 60 °C for 16 hours. The desired product was detected by LCMS. The residue was purified by reversed-phase flash chromatography to give N,4-dimethyl-2-{[(1S,3S)-3-({5-[2-oxo-2-(pyrrolo-1-yl)ethyl]pyridin-2-yl}amino)cyclopentyl}amino}pyrimidine-5-carboxamide (4.4 mg).

[0776] LCMS(ESI,m / z):[M+H] + =434.22

[0777] 1 H NMR (400MHz, Methanol-d4) δ8.28(s,1H),7.89(s,1H),7.58–7.38(m,3H),6.55(d,J=8.8Hz,1H),6.33(s,2H),4.49(s,1 H),4.32–4.24(m,1H),4.13(s,2H),2.88(s,3H),2.47(s,3H),2.40–2.26(m,2H),2.26–1.92(m,2H),1.64–1.48(m,2H).

[0778] Example 81

[0779] 1. Synthesis of compound a

[0780] At room temperature, N,N-diisopropylethylamine (1.5 g, 11.6 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (4.4 g, 11.6 mmol) were added in portions to a stirred solution of 1,3-thiazol-2-carboxylic acid (1.0 g, 7.7 mmol) and 6-chloropyridinium-3-amine (1.0 g, 7.7 mmol) in N,N-dimethylformamide (10 mL). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water at room temperature. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure after filtration. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (1:1) to give a yellow solid N-(6-chloropyridinium-3-yl)thiazol-2-carboxamide (1.5 g, 65% purity).

[0781] LCMS(ESI,m / z):[M+H] + =240.00

[0782] 2. Synthesis of compound b

[0783] Iodine (3.2 g, 22.5 mmol) was added in portions to a stirred solution of N-(6-chloropyridin-3-yl)thiazolyl-2-carboxamide (1.8 g, 7.5 mmol) and potassium tert-butoxide (2.5 g, 22.5 mmol) in N,N-dimethylformamide (20 mL). The resulting mixture was stirred overnight at room temperature. The mixture was then concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water, 10%–90% gradient, 10 min; detector, UV 254 nm. The result was N-(6-chloropyridin-3-yl)-N-methylthiazolyl-2-carboxamide (450 mg, 91% purity), as a pale yellow solid.

[0784] LCMS(ESI,m / z):[M+H] + =254.05

[0785] 3. Synthesis of Compound 134

[0786] At room temperature and under nitrogen atmosphere, N-(2,6-dimethylphenyl)-6-hydroxypyridine-2-carboxamide (6 mg, 0.02 mmol), cuprous iodide (3 mg, 0.02 mmol), and potassium carbonate (218 mg, 1.6 mmol) were added to a stirred mixture of N-(6-chloropyridin-3-yl)-N-methylthiazol-2-carboxamide (100 mg, 0.4 mmol) and (1S,3S)-N1-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine (96 mg, 0.4 mmol) in dimethyl sulfoxide (5 mL). The resulting mixture was stirred at 110 °C under nitrogen atmosphere for 2 hours. The mixture was filtered, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography to give N-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-N-methyl-1,3-thiazolyl-2-carboxamide (13.7 mg).

[0787] LCMS(ESI,m / z):[M+H] + =462.20

[0788] 1H NMR (400MHz, DMSO-d6) δ8.23(s,2H),8.15–7.89(m,1H),7.88–7.68(m,2H),7.46(d,J=7.2Hz,1H),7.31(d,J=8.7Hz,1H),7.15–6.98(m,1H ),6.75(d,J=6.7Hz,1H),6.42(d,J=8.8Hz,1H),4.37–4.17(m,2H),3.30(s,3H),2.15–2.02(m,2H),1.94–1.73(m,2H),1.59–1.38(m,2H).

[0789] Example 82

[0790] 1. Synthesis of Compound 139

[0791] To a solution of (6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)acetic acid (80 mg, 0.2 mmol) and 1H,2H,3H-pyrrolo[2,3-b]pyridine (25 mg, 0.2 mmol) in dichloromethane (1 mL), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (120 mg, 0.3 mmol) and N,N-diisopropylethylamine (81 mg, 0.6 mmol) were added. The resulting mixture was stirred at room temperature in air for 2 hours. The mixture was then concentrated under reduced pressure. The product was purified by flash chromatography to obtain 2-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-{2H,3H-pyrrolo[2,3-b]pyridin-1-yl} acetone (10.4 mg).

[0792] LCMS(ESI,m / z): [M+H] + =482.25

[0793] 1H NMR(400MHz, DMSO-d6)δ8.23(s,2H),8.16(dd,J=5.1,1.6Hz,1H),7.85(d,J=2.3H z,1H),7.65–7.62(m,1H),7.45(d,J=7.2Hz,1H),7.27(dd,J=8.5,2.4Hz,1H),7.24 –6.73(m,2H),6.39(d,J=7.9Hz,2H),4.37–4.14(m,4H),3.97(dd,J=9.2,7.9Hz,2H ), 3.04(t,J=8.5Hz,2H),2.09–2.01(m,2H),1.84–1.72(m,2H),1.48–1.30(m,2H).

[0794] Example 83

[0795] 1. Synthesis of Compound 144

[0796] To a solution of (50 mg, 0.1 mmol) acetic acid and morpholine (11 mg, 0.1 mmol) in dichloromethane (1 mL) at room temperature and air, N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (75 mg, 0.1 mmol) and N,N-diisopropylethylamine (51 mg, 0.3 mmol) were added. The resulting mixture was stirred at room temperature and air for 2 hours. The mixture was then concentrated under reduced pressure. The product was purified by flash chromatography to obtain 2-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-(morpholin-4-yl) acetone (12.7 mg).

[0797] LCMS(ESI,m / z): [M+H] + =449.25

[0798] 1 H NMR (400MHz, DMSO-d6) δ8.23(s,2H),7.78(d,J=2.3Hz,1H),7.45(d,J=7.2Hz,1H),7.26–6.81(m,2H),6.41(dd,J= 7.7,4.0Hz,2H),4.26–4.12(m,2H),3.57–3.38(m,10H),2.10–1.99(m,2H),1.84–1.71(m,2H),1.58–1.42(m,2H).

[0799] Example 84

[0800] 1. Synthesis of Compound 145

[0801] To a solution of (100 mg, 0.2 mmol) acetic acid and piperazine (22 mg, 0.2 mmol) in dichloromethane (1 mL) at room temperature and air, N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (150 mg, 0.3 mmol) and N,N-diisopropylethylamine (102 mg, 0.7 mmol) were added. The resulting mixture was stirred at room temperature and air for 2 hours. The mixture was then concentrated under reduced pressure. The product was purified by flash chromatography to obtain 2-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-(piperazin-1-yl)acetone (11.5 mg).

[0802] LCMS(ESI,m / z): [M+H] + =448.25

[0803] 1 H NMR (400MHz, DMSO-d6) δ8.22(s,2H),7.78(d,J=2.3Hz,1H),7.44(d,J=7.2Hz,1H),7.30–6.78(m,2H),6.50–6.26(m,2H),4.25–4.10( m,2H),3.46(s,3H),3.37(dt,J=10.4,4.6Hz,4H),3.28(s,1H),2.58(s,3H),2.10–2.00(m,2H),1.84–1.70(m,2H),1.60–1.44(m,2H).

[0804] Example 85

[0805] 1. Synthesis of Compound 151

[0806] To a solution of (6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)acetic acid (100 mg, 0.2 mmol) and 2H,3H,4H-pyrido[3,2-b][1,4]oxazine (35 mg, 0.2 mmol) in dichloromethane (1 mL), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (150 mg, 0.3 mmol) and N,N-diisopropylethylamine (102 mg, 0.7 mmol) were added. The resulting mixture was stirred at room temperature in air for 2 hours. The mixture was then concentrated under reduced pressure. The product was purified by flash chromatography to give 2-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-{2H,3H-pyrido[3,2-b][1,4]oxazin-4-yl} acetone (13.5 mg, 10.29% yield).

[0807] LCMS(ESI,m / z): [M+H] + =498.25

[0808] 1 H NMR(400MHz, DMSO-d6)δ8.22(s,2H),8.01(dd,J=4.7,1.6Hz,1H),7.75(d,J=2.3Hz, 1H),7.44(d,J=7.2Hz,1H),7.34(dd,J=8.1,1.6Hz,1H),7.27–7.20(m,1H),7.18–6.8 2(m,2H),6.47–6.41(m,1H),6.38(d,J=8.6Hz,1H),4.34–4.14(m,4H),4.11(s,2H),3 .94(dd,J=5.3,3.9Hz,2H),2.08–1.99(m,2H),1.83–1.79(m,2H),1.57–1.35(m,2H).

[0809] Example 86

[0810] 1. Synthesis of compound a

[0811] Under a nitrogen atmosphere, at room temperature, a solution of 6-chloropyridin-3-amine (1.0 g, 7.8 mmol) and 1-fluoro-3-iodobenzene (1.7 g, 7.8 mmol) was added to 10 mL of dioxane with stirring. Tris(dibenzylacetone)dipalladium (356.2 mg, 0.4 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (450.1 mg, 0.8 mmol), and cesium carbonate (7.6 g, 23.3 mmol) were added in portions. The resulting mixture was stirred at 110 °C for 2 hours. The mixture was filtered, and the filter cake was washed with methyl cyanide. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (5 / 1) to give 6-chloro-N-(3-fluorophenyl)pyridin-3-amine (1.3 g, 75.1% yield) as a white solid.

[0812] LCMS(ESI,m / z): [M+H] + =223.15

[0813] 2. Synthesis of compound b

[0814] To a stirred solution of 6-chloro-N-(3-fluorophenyl)pyridin-3-amine (500 mg, 2.2 mmol) and cesium carbonate (2.2 g, 6.7 mmol) in acetonitrile (15 mL), 1-methylimidazolium-4-carboxyl chloride (503.2 mg, 3.5 mmol) was added in portions at room temperature. The resulting mixture was stirred at 80 °C for 2 h in air. The desired product was detected by liquid chromatography-mass spectrometry. The resulting mixture was filtered, and the filter cake was washed with acetonitrile. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water, 10% to 50% gradient over 10 min; detector, UV 254 nm, to give N-(6-chloropyridin-3-yl)-N-(3-fluorophenyl)-1-methylimidazolium-4-carboxamide (200 mg, 26.93% yield) as a white solid.

[0815] LCMS(ESI,m / z): [M+H] + =331.00

[0816] 3. Synthesis of Compound 73-2

[0817] To a stirred solution of N-(6-chloropyridin-3-yl)-N-(3-fluorophenyl)-1-methylimidazolium-4-carboxamide (280 mg, 0.8 mmol) and (1S,3S)-N1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclopentane-1,3-diamine (206.8 mg, 0.8 mmol) in tetrahydrofuran (4 mL), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (67.3 mg, 0.09 mmol) and sodium tert-butoxide (325.4 mg, 3.4 mmol) was added fractionally at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 2 hours. The mixture was filtered, and the filter cake was washed with acetonitrile. The filtrate was concentrated under reduced pressure. The crude product (mg) was purified by preparative high performance liquid chromatography to obtain N-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-N-(3-fluorophenyl)-1-methylimidazol-4-carboxamide (8.2 mg).

[0818] LCMS(ESI,m / z): [M+H] + =539.50

[0819] 1 H NMR (400MHz, DMSO-d6) δ8.23(s,2H),7.81(d,J=2.6Hz,1H),7.46(d,J=7.4Hz,2H),7.39–7.21(m,3H),7.14–6.84(m,4H),6.73(d ,J=6.3Hz,1H),6.43(d,J=8.9Hz,1H),4.32–4.22(m,2H),3.59(s,3H),2.17–2.05(m,2H),1.92–1.79(m,2H),1.57–1.44(m,2H).

[0820] Example 87

[0821] 1. Synthesis of compound a

[0822] To a stirred solution of 6-chloropyridin-3-amine (1.0 g, 7.8 mmol) and benzene, a solution of 1-fluoro-4-iodobenzene (1.7 g, 7.8 mmol) in dioxane (10 mL) was added fractionally at room temperature under a nitrogen atmosphere, followed by tris(dibenzylacetone)dipalladium (356.2 mg, 0.4 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (450.1 mg, 0.8 mmol), and cesium carbonate (7.6 g, 23 mmol). The resulting mixture was stirred at 110 °C for 2 hours. The mixture was filtered, and the filter cake was washed with methyl cyanide. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (5:1), to give 6-chloro-N-(3-fluorophenyl)pyridin-3-amine (800 mg, 46.19% yield) as a white solid.

[0823] LCMS(ESI,m / z): [M+H] + =223.00

[0824] 2. Synthesis of compound b

[0825] To a stirred solution of 6-chloro-N-(4-fluorophenyl)pyridin-3-amine (400 mg, 1.8 mmol) and cesium carbonate (3.5 g, 10.8 mmol) in acetonitrile (15 mL), 1-methylimidazolium-4-carboxyl chloride (800 mg, 5.5 mmol) was added in portions at room temperature. The resulting mixture was stirred at 80 °C for 2 h in air. The desired product was detected by liquid chromatography-mass spectrometry. The resulting mixture was filtered, and the filter cake was washed with acetonitrile. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water, 10% to 50% gradient over 10 min; detector, 254 nm UV, yielding N-(6-chloropyridin-3-yl)-N-(4-fluorophenyl)-1-methylimidazolium-4-carboxamide (200 mg, 33.66% yield) as a white solid.

[0826] LCMS(ESI,m / z): [M+H] + =331.05

[0827] 3. Synthesis of compound 73-3

[0828] To a stirred solution of N-(6-chloropyridin-3-yl)-N-(4-fluorophenyl)-1-methylimidazolium-4-carboxamide (190 mg, 0.6 mmol) and (1S,3S)-N1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclopentane-1,3-diamine (140.3 mg, 0.6 mmol) in tetrahydrofuran (3 mL), [2-(dicyclohexylphosphine)-3-tert-butoxy-6-methoxy-2',6'-diisopropyl-1,1'-biphenyl](4-((2-(trimethylsilyl)ethoxy)carbonyl)phenyl-1-yl)palladium bromide (54.1 mg, 0.06 mmol) and sodium trimethylsilanolate (257.8 mg, 2.3 mmol) were added in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 50 °C for 2 hours. The mixture was filtered, and the filter cake was washed with acetonitrile. The filtrate was concentrated under reduced pressure. The crude product (mg) was subjected to preparative high-performance liquid chromatography to obtain N-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-N-(4-fluorophenyl)-1-methylimidazolium-4-carboxamide (10.2 mg).

[0829] LCMS(ESI,m / z): [M+H] + =539.50

[0830] 1 H NMR (400MHz, DMSO-d6) δ8.23(s,2H),7.84(d,J=2.6Hz,1H),7.54(s,1H),7.46(d,J=7.2Hz,1H),7.38–6.85(m,8H) ,6.49(d,J=8.9Hz,1H),4.32–4.21(m,2H),3.59(s,3H),2.15–2.04(m,2H),1.93–1.80(m,2H),1.57–1.45(m,2H).

[0831] Example 88

[0832] 1. Synthesis of compound a

[0833] Under a nitrogen atmosphere, a solution of methyl 1H-pyrrolo[3,2-b]pyridine-3-carboxylate (3.0 g, 17.0 mmol) in tetrahydrofuran (1 mL) was added in portions to sodium hydride (0.5 g, 20.4 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 30 min. [2-(chloromethoxy)ethyl]trimethylsilane (4.3 g, 25.5 mmol) was added in portions to the mixture at 0 °C over 1 min. The resulting mixture was stirred at room temperature for another 1 h. The mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography to give the crude product methyl 1-{[2-(trimethylsilyl)ethoxy]methyl}pyrrolo[3,2-b]pyridine-3-carboxylate (3.6 g).

[0834] LCMS(ESI,m / z): [M+H] + =307.14

[0835] 2. Synthesis of compound b

[0836] At room temperature and in air, a stirred solution of methyl 1-{[2-(trimethylsilyl)ethoxy]methyl}pyrrolo[3,2-b]pyridine-3-carboxylic acid (3.6 g, 11.7 mmol) and potassium hydroxide (0.7 g, 11.7 mmol) in methanol (18 mL) was added in portions to water (18 mL). The resulting mixture was stirred at 60 °C for 2 hours. The mixture was neutralized to pH 7 with hydrochloric acid (aqueous solution). The aqueous layer was extracted with ethyl acetate. The resulting mixture was concentrated under reduced pressure. 1-{[2-(trimethylsilyl)ethoxy]methyl}pyrrolo[3,2-b]pyridine-3-carboxylic acid (3.3 g, crude product) was given as a white solid.

[0837] LCMS(ESI,m / z): [M+H] + =293.25

[0838] 3. Synthesis of compound c

[0839] To a stirred solution of 6-chloropyridin-3-amine (3.3 g, 25.7 mmol) and 1-{[2-(trimethylsilyl)ethoxy]methyl}pyrrolo[3,2-b]pyridine-3-carboxylic acid (7.5 g, 25.7 mmol) in dichloromethane (33 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.0 g, 38.5 mmol) was added fractionally at room temperature under air. The resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (1:1), to give N-(6-chloropyridin-3-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrrolo[3,2-b]pyridine-3-carboxamide (3.8 g, crude product) as a white solid.

[0840] LCMS(ESI,m / z): [M+H] + =403.20

[0841] 4. Synthesis of compound d

[0842] Under a nitrogen atmosphere, iodomethane (4.0 g, 28.3 mmol) was added in portions to a solution of N,N-dimethylformamide (40 mL) containing N-(6-chloropyridin-3-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrrolo[3,2-b]pyridine-3-carboxamide (3.8 g, 9.4 mmol) and potassium tert-butoxide (3.2 g, 28.3 mmol). The resulting mixture was stirred at room temperature for 2 hours. The desired product was detected by LCMS. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with water and dried over anhydrous sodium sulfate. The filtrate was then concentrated under reduced pressure after filtration. The residue was purified by silica gel column chromatography and eluted with petroleum ether / ethyl acetate (1:1) to give N-(6-chloropyridin-3-yl)-N-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrrolo[3,2-b]pyridine-3-carboxamide (1.9 g, crude product) as a yellow solid.

[0843] LCMS(ESI,m / z): [M+H] + =417.25

[0844] 5. Synthesis of compound e

[0845] To a stirred solution of N-(6-chloropyridin-3-yl)-N-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrrolo[3,2-b]pyridine-3-carboxamide (300 mg, 0.7 mmol) and (1S,3S)-N1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclopentane-1,3-diamine (175.7 mg, 0.7 mmol) in tetrahydrofuran (5 mL), [2-(dicyclohexylphosphine)-3-tert-butoxy-6-methoxy-2',6'-diisopropyl-1,1'-biphenyl](4-((2-(trimethylsilyl)ethoxy)carbonyl)phenyl-1-yl)palladium bromide (68.0 mg, 0.07 mmol) and sodium trimethylsilanolate (161.4 mg, 1.4 mmol) were added in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 50°C for 2 hours. The mixture was filtered, and the filter cake was washed with acetonitrile. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (1:1), to give N-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-N-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrrolo[3,2-b]pyridine-3-carboxamide (240 mg, yield 53.39%) as a brown oil.

[0846] LCMS(ESI,m / z): [M+H] + =625.40

[0847] 6. Synthesis of Compound 76

[0848] Under ambient air at room temperature, N-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-N-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrrolo[3,2-b]pyridine-3-carboxamide (120 mg, 0.2 mmol) was added in portions to a stirred solution of trifluoroacetic acid (2 mL). The resulting mixture was stirred for 1 hour at room temperature. The mixture was then concentrated under vacuum. The crude product (mg) was purified by preparative high-performance liquid chromatography to give N-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-N-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (7.2 mg).

[0849] LCMS(ESI,m / z): [M+H] + =495.50

[0850] 1H NMR(400MHz,DMSO-d6)δ11.50(s,1H),8.32–8.25(m,1H),8.22(s,2H),7.77(d,J=2.6Hz,1 H),7.72(d,J=8.1Hz,1H),7.55(s,1H),7.42(d,J=7.2Hz,1H),7.27(dd,J=8.8,2.7Hz,1H), 7.23–6.84(m,2H),6.50(d,J=6.9Hz,1H),6.28(d,J=8.8Hz,1H),4.25(q,J=6.9Hz,1H),4. 14(q,J=6.4Hz,1H),3.31(s,3H),2.11–1.99(m,2H),1.87–1.70(m,2H),1.53–1.32(m,2H).

[0851] Example 89

[0852] 1. Synthesis of compound 92-2-15

[0853] To a stirred solution of 2-bromo-[1,2,4]triazolo[1,5-a]pyrazine (100 mg, 0.5 mmol) and N-(6-{[(1S,3S)-3-aminocyclopentyl]amino}pyridin-3-yl)-N,1-dimethylimidazol-4-carboxamide (158.0 mg, 0.5 mmol) in tetrahydrofuran (2 mL), [2-(dicyclohexylphosphine)-3-tert-butoxy-6-methoxy-2',6'-diisopropyl-1,1'-biphenyl](4-((2-(trimethylsilyl)ethoxy)carbonyl)phenyl-1-yl)palladium bromide (47.5 mg, 0.05 mmol) and sodium tert-butoxide (193.2 mg, 2.0 mmol) were added in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 50 °C for 2 hours. The mixture was filtered, and the filter cake was washed with acetonitrile. The filtrate was concentrated under reduced pressure. The crude product (mg) was purified by preparative high performance liquid chromatography to obtain N,1-dimethyl-N-(6-{[(1S,3S)-3-{[1,2,4]triazolo[1,5-a]pyrazin-2-ylamino}cyclopentyl]amino}pyridin-3-yl)imidazol-4-carboxamide (8.1 mg).

[0854] LCMS(ESI,m / z): [M+H] + =433.40

[0855] 1H NMR (400MHz, DMSO-d6) δ8.87(d,J=1.3Hz,1H),8.74(dd,J=4.3,1.4Hz,1H),7.99(d,J=4.3Hz,1H),7.72(s,1H),7.43(s,1H),7.29–7.10(m,3H),6. 63(d,J=6.9Hz,1H),6.42(d,J=8.8Hz,1H),4.29–4.17(m,2H),3.57(s,3H ),3.32(s,3H),2.19–2.08(m,2H),1.99–1.83(m,2H),1.63–1.46(m,2H).

[0856] Example 90

[0857] 1. Synthesis of Compound 94

[0858] N-[(1S,3S)-3-({5-[2-(2,5-dihydropyrrolo-1-yl)-2-oxoethyl]pyridin-2-yl}amino)cyclopentyl]-N″-hydroxyguanidine (150 mg, 0.4 mmol) was dissolved in difluoroacetic anhydride (2 mL) and stirred in air at room temperature for 1 min. The reaction was quenched with water and carried out at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water (0.1% ammonia) in a 10% to 50% gradient, 15 min; detector, UV. 254 nm yielded 2-(6-{[(1S,3S)-3-{[5-(difluoromethyl)-1,2,4-oxadiazol-3-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-(2,5-dihydropyrrole-1-yl)acetone (30 mg, 17.03% yield), an off-white semi-solid.

[0859] LCMS(ESI,m / z): [M+H] + =405.20

[0860] 2. Synthesis of Compound 94

[0861] A solution of 2-(6-{[(1S,3S)-3-{[5-(difluoromethyl)-1,2,4-oxadiazol-3-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-(2,5-dihydropyrrolo-1-yl)acetone (27 mg, 0.06 mmol) and manganese dioxide (174 mg, 2.0 mmol) in dichloromethane (1 mL) was stirred overnight in air at room temperature. The resulting mixture was filtered, and the filter cake was washed with dichloromethane. The filtrate was concentrated under reduced pressure. Column: YMC-Actus Triart C18 ExRS 5 μm, 30 mm × 150 mm; Mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient (B%): from 25% B to 45% B over 7 min; wavelength: 254 nm / 220 nm; RT1 (min): 6.85 to yield 2-(6-{[(1S,3S)-3-{[5-(difluoromethyl)-1,2,4-oxadiazol-3-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-(pyrrolo-1-yl)acetone (5.1 mg).

[0862] LCMS(ESI,m / z):[M+H] + =403.20

[0863] 1 H NMR (400MHz, DMSO-d6) δ7.90(d,J=2.4Hz,1H),7.55–7.50(m,2H),7.43–7.13(m,3H),6.53(d,J=6.9Hz,1H),6.42(dd,J=8.6,0.7Hz,1H),6.36–6. 31(m,2H),4.26(q,J=6.6Hz,1H),4.12(s,2H),3.91(q,J=6.4Hz,1H),2.1 6–2.03(m,2H),1.94–1.87(m,1H),1.82–1.74(m,1H),1.58–1.42(m,2H).

[0864] Example 91

[0865] 1. Synthesis of compound a

[0866] A solution of N-(6-{[(1S,3S)-3-aminocyclopentyl]amino}pyridin-3-yl)-N,1-dimethylimidazolium-4-carboxamide (1.0 g, 3.1 mmol) and diisopropylethylamine (822 mg, 6.3 mmol) in tetrahydrofuran (10 mL) was stirred for 1 minute at room temperature in air. Then, carbon nitride bromide (336 mg, 3.1 mmol) was added in portions to the mixture over 1 minute. The resulting mixture was stirred for 2 hours at room temperature. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with dichloromethane / methanol (5:1), to give N-(6-{[(1S,3S)-3-(cyanoamino)cyclopentyl]amino}pyridin-3-yl)-N,1-dimethylimidazolium-4-carboxamide (230 mg, 21.31% yield) as a yellow oil.

[0867] LCMS(ESI,m / z): [M+H] + =340.30

[0868] 2. Synthesis of compound b

[0869] A solution of N-(6-{[(1S,3S)-3-(cyanoamino)cyclopentyl]amino}pyridin-3-yl)-N,1-dimethylimidazol-4-carboxamide (230 mg, 0.6 mmol), triethylamine (137 mg, 1.3 mmol), and hydroxylamine hydrochloride (56 mg, 0.8 mmol) in ethanol (3 mL) was stirred overnight at 50 °C under air. The mixture was cooled to room temperature. The mixture was concentrated under reduced pressure to give N-(6-{[(1S,3S)-3-(N”-hydroxycarbamoylimino)cyclopentyl]amino}pyridin-3-yl)-N,1-dimethylimidazol-4-carboxamide (210 mg, crude product) as an orange oil.

[0870] LCMS(ESI,m / z): [M+H] + =373.35

[0871] 3. Synthesis of compound c

[0872] N-(6-{[(1S,3S)-3-(N”-hydroxyureaiminocarbamate)cyclopentyl]amino}pyridin-3-yl)-N,1-dimethylimidazolium-4-carboxamide (200 mg, 0.5 mmol) was dissolved in trichloroacetic anhydride (2 mL) and stirred at 60 °C for 1 hour in air. The mixture was cooled to room temperature. The resulting mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give N,1-dimethyl-N-(6-{[(1S,3S)-3-{[5-(trichloromethyl)-1,2,4-oxadiazol-3-yl]amino}cyclopentyl]amino}pyridin-3-yl)imidazolium-4-carboxamide (150 mg, crude product) as an orange oil.

[0873] LCMS(ESI,m / z): [M+H] + =499.15

[0874] 4. Synthesis of compound 97-15

[0875] N,1-Dimethyl-N-(6-{[(1S,3S)-3-{[5-(trichloromethyl)-1,2,4-oxadiazol-3-yl]amino}cyclopentyl]amino}pyridin-3-yl)imidazol-4-carboxamide (140 mg, 0.2 mmol) was dissolved in methylamine (31% in methanol) (2 mL) and stirred at 60 °C for 1 hour under air. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. Column: XBridge BEH C18 OBD preparative column, 5 μm, 30 mm × 150 mm; Mobile phase A: water (10 mmol / L ammonium bicarbonate + 0.1% ammonia), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient (B%): from 5% B to 25% B over 8 min; wavelength: 254 / 220 nm; RT1 (min): 7.37. N,1-Dimethyl-N-(6-{[(1S,3S)-3-{[5-(methylamino)-1,2,4-oxadiazol-3-yl]amino}cyclopentyl]amino}pyridin-3-yl)imidazol-4-carboxamide (13.4 mg).

[0876] LCMS(ESI,m / z):[M+H] + =412.20

[0877] 1H NMR (400MHz, DMSO-d6) δ7.80–7.70(m,2H),7.44(s,1H),7.23(dd,J=8.8,2.7Hz,2H),6.57(d,J=6.9Hz,1H),6.45–6.30(m,2H),4.19–4.11(m ,1H),3.79–3.71(m,1H),3.57(s,3H),3.33(s,3H),2.77(s,3H),2.04– 1.92(m,2H),1.86–1.78(m,1H),1.74–1.66(m,1H),1.55–1.32(m,2H).

[0878] Example 92

[0879] 1. Synthesis of Compound 138

[0880] At room temperature and in air, N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (150 mg, 0.3 mmol) and N,N-diisopropylethylamine (102 mg, 0.7 mmol) were added to a solution of (6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)acetic acid (100 mg, 0.2 mmol) and indoline (31 mg, 0.2 mmol) in dichloromethane (1 mL). The resulting mixture was stirred at room temperature and in air for 2 hours. The sample was purified by flash chromatography to obtain a white solid 2-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-(2,3-dihydroindol-1-yl)acetone (13.1 mg).

[0881] LCMS(ESI,m / z): [M+H] + =481.20

[0882] 1 H NMR (400MHz, DMSO-d6) δ8.23(s,2H),8.04(d,J=8.0Hz,1H),7.84(d,J=2.3Hz,1H),7.46(d,J=7.2Hz,1H),7.34–6.81(m,5H),6.44(t,J=7.4Hz ,2H),4.27–4.15(m,2H),4.17(t,J=8.5Hz,2H),3.63(s,2H),3.16(t,J =8.5Hz,2H),2.20–2.04(m,2H),1.96–1.78(m,2H),1.62–1.38(m,2H).

[0883] Example 93

[0884] 1. Synthesis of compound a

[0885] A methanol solution (25 mL) of 4-chloro-5H,6H,7H-pyrrolo[2,3-d]pyrimidine (500 mg, 3.2 mmol) and palladium on carbon (99 mg, 0.9 mmol) was stirred for 6 hours at room temperature under a hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure to give 5H,6H,7H-pyrrolo[2,3-d]pyrimidine (350 mg, 89.90% yield) as a grayish-white solid.

[0886] LCMS(ESI,m / z): [M+H] + =122.10

[0887] 2. Synthesis of Compound 141

[0888] To a solution of (100 mg, 0.2 mmol) acetic acid and 6,7-dihydro-5H-pyrrolo[2,3-D]pyrimidine (31 mg, 0.2 mmol) in dichloromethane (1 mL), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (150 mg, 0.3 mmol) and N,N-diisopropylethylamine (102 mg, 0.7 mmol) were added. The resulting mixture was stirred at room temperature in air for 2 hours. The mixture was then concentrated under reduced pressure. The product was purified by flash chromatography to obtain 2-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-{5H,6H-pyrrolo[2,3-d]pyrimidin-7-yl} acetone (12.2 mg).

[0889] LCMS(ESI,m / z):[M+H] + =483.20

[0890] 1H NMR(400MHz, DMSO-d6)δ8.75(d,J=1.0Hz,1H),8.47(d,J=1.3Hz,1H),8.22(s, 2H),7.85(d,J=2.4Hz,1H),7.44(d,J=7.2Hz,1H),7.26(dd,J=8.5,2.4Hz,1H), 7.11–6.90(m,1H),6.50–6.35(m,2H),4.35–4.20(m,4H),3.98(dd,J=9.3,7.9 Hz,2H),3.32(s,2H),2.09–2.01(m,2H),1.91–1.78(m,2H),1.55–1.36(m,2H).

[0891] Example 94

[0892] 1. Synthesis of compound a

[0893] To a stirred solution of 5-methyl-1,3-thiazolyl-2-carboxylic acid (25 mg, 0.2 mmol) and 6-chloropyridin-3-amine (22.45 mg, 0.175 mmol) in dichloromethane (2 mL), HATU (99.6 mg, 0.3 mmol) and diisopropylethylamine (67.7 mg, 0.5 mmol) were added fractionally at room temperature under air. The resulting mixture was stirred at room temperature under air for 2 hours. The desired product was detected by liquid chromatography-mass spectrometry. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (2:1), to give a yellow solid N-(6-chloropyridin-3-yl)-5-methyl-1,3-thiazolyl-2-carboxamide (4.1 g, 45.71% yield).

[0894] LCMS(ESI,m / z): [M+H] + =254.10

[0895] 2. Synthesis of compound b

[0896] To a stirred solution of N-(6-chloropyridin-3-yl)-5-methyl-1,3-thiazolyl-2-carboxamide (2 g, 7.9 mmol) and potassium tert-butoxide (1.3 g, 11.9 mmol) in N,N-dimethylformamide (15 mL), iodomethane (1 mL, 16.1 mmol) was added in portions under air at room temperature. The resulting mixture was stirred for 2 hours under air at room temperature. The desired product was detected by liquid chromatography-mass spectrometry. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, methanol in water, gradient from 20% to 65% over 10 minutes; detector, 254 nm UV, yielding N-(6-chloropyridin-3-yl)-N,5-dimethyl-1,3-thiazolyl-2-carboxamide (1.6 g, 75.81% yield) as a yellow solid.

[0897] LCMS(ESI,m / z): [M+H] + =268.10

[0898] 3. Synthesis of Compound 152

[0899] To a stirred solution of N-(6-chloropyridin-3-yl)-N,5-dimethyl-1,3-thiazolyl-2-carboxamide (60 mg, 0.2 mmol) and (1S,3S)-N1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclopentane-1,3-diamine (54.7 mg, 0.2 mmol) in tetrahydrofuran (1 mL), 3-chloropyridine, {1,3-bis[2,6-bis(hept-4-yl)phenyl]-4,5-dichloro-2,3-dihydro-1H-imidazol-2-yl}dichloropalladium (21.8 mg, 0.02 mmol) and cesium carbonate (219.1 mg, 0.7 mmol) were added in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 90 °C. The mixture was filtered, and the filter cake was washed with acetonitrile. The filtrate was concentrated under reduced pressure. The crude product (mg) was purified by preparative high performance liquid chromatography to obtain N-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-N,5-dimethyl-1,3-thiazolyl-2-carboxamide (6.0 mg).

[0900] LCMS(ESI,m / z): [M+H] + =474.30

[0901] 1H NMR (400MHz, DMSO-d6) δ8.23(s,2H),7.81–7.73(m,1H),7.46(d,J=7.2Hz,1H),7.42–7.27(m,2H),7.15–6.90(m,1H),6.72(d,J=6.9H z,1H),6.41(d,J=8.9Hz,1H),4.32–4.24(m,2H),3.27(s,3H),2.40(s,3H),2.17–2.04(m,2H),1.90-1.82(m,2H),1.54–1.45(m,2H).

[0902] Example 95

[0903] 1. Synthesis of compound a

[0904] A solution of 2-bromomalondialdehyde (5.0 g, 33.1 mmol) and ethyl thiocarbamate (4.4 g, 33.1 mmol) was placed in 50 mL of 1,2-dimethoxyethane and stirred in air at room temperature for 8 hours. The desired product was detected by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the mixture was quenched with water at room temperature. The resulting mixture was extracted with dichloromethane. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give a yellow solid crude product, ethyl 5-carboxaldehyde-1,3-thiazolyl-2-carboxylic acid ester (3.8 g).

[0905] LCMS(ESI,m / z): [M+H] + =186.00

[0906] 2. Synthesis of compound b

[0907] A solution (80 mL) of ethyl 5-formaldehyde-1,3-thiazol-2-carboxylate (3.8 g, 20.5 mmol) and diethylaminothiotrifluoride (6.6 g, 41.0 mmol) in dichloromethane was stirred in air at room temperature for 3 hours. The target product was detected by liquid chromatography-mass spectrometry. The reaction was quenched with saturated sodium bicarbonate aqueous solution at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL). The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with water and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give a yellow oily crude product, ethyl 5-(difluoromethyl)-1,3-thiazol-2-carboxylate (2.6 g).

[0908] LCMS(ESI,m / z): [M+H] + =208.05

[0909] 3. Synthesis of compound c

[0910] A solution of ethyl 5-(difluoromethyl)-1,3-thiazolyl-2-carboxylate (1.2 g, 5.8 mmol) in tetrahydrofuran (20 mL) / water (5 mL) and lithium hydroxide hydrate (1.2 g, 28.9 mmol) was stirred at 50 °C in air for 2 hours. The desired product was detected by liquid chromatography-mass spectrometry. The mixture was acidified to pH 2 with 2 M hydrochloric acid. The resulting mixture was concentrated under vacuum to give 5-(difluoromethyl)-1,3-thiazolyl-2-carboxylic acid (0.8 g, crude product) as a yellow solid. The crude product was used directly in the next reaction without further purification.

[0911] LCMS(ESI,m / z): [M+H] + =180.15

[0912] 4. Synthesis of compound d

[0913] To a stirred solution of 5-(difluoromethyl)-1,3-thiazolyl-2-carboxylic acid (1.2 g, 6.7 mmol) and 6-chloropyridin-3-amine (1.0 g, 8.0 mmol) in N,N-dimethylformamide (20 mL), HATU (3.8 g, 10.0 mmol) and diisopropylethylamine (2.6 g, 20.1 mmol) were added fractionally under air at room temperature. The resulting mixture was stirred at 60 °C for 2 h under air. The desired product was detected by liquid chromatography-mass spectrometry. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (2:1), to give N-(6-chloropyridin-3-yl)-5-(difluoromethyl)-1,3-thiazolyl-2-carboxamide (1.2 g, 61.84% yield) as a white solid.

[0914] LCMS(ESI,m / z): [M+H] + =290.10

[0915] 5. Synthesis of compound e

[0916] Iodimethane (1.5 g, 10.3 mmol) was added dropwise to a stirred solution of N-(6-chloropyridin-3-yl)-5-(difluoromethyl)-1,3-thiazol-2-carboxamide (1.0 g, 3.4 mmol) and potassium tert-butoxide (1.2 g, 10.3 mmol) in dimethylformamide (20 mL) under air at 0 °C. The resulting mixture was stirred at room temperature under air for 2 h. The desired product was detected by liquid chromatography-mass spectrometry. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water, gradient from 10% to 50% over 30 min; detector, 254 nm UV, yielding N-(6-chloropyridin-3-yl)-5-(difluoromethyl)-N-methyl-1,3-thiazol-2-carboxamide (350 mg, 33.38% yield) as a yellow oil.

[0917] LCMS(ESI,m / z): [M+H] + =304.10

[0918] 6. Synthesis of Compound 154

[0919] To a stirred solution of N-(6-chloropyridin-3-yl)-5-(difluoromethyl)-N-methyl-1,3-thiazolyl-2-carboxamide (60 mg, 0.2 mmol) and (1S,3S)-N1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclopentane-1,3-diamine (48.3 mg, 0.2 mmol) in dioxane, 3-chloropyridine; {1,3-bis[2,6-bis(hept-4-yl)phenyl]-4,5-dichloro-2,3-dihydro-1H-imidazol-2-yl}dichloropalladium (19.2 mg, 0.02 mmol) and cesium carbonate (193.1 mg, 0.6 mmol) were added in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 90 °C. The mixture was filtered, and the filter cake was washed with methyl cyanide. The filtrate was concentrated under reduced pressure. The crude product (mg) was purified by preparative high performance liquid chromatography to obtain N-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-5-(difluoromethyl)-N-methyl-1,3-thiazolyl-2-carboxamide (5.3 mg).

[0920] LCMS(ESI,m / z): [M+H] + =512.30

[0921] 1H NMR (400MHz, DMSO-d6) δ8.23(s,2H),8.04(t,J=2.1Hz,1H),7.83(d,J=2.7Hz,1H),7.51–7.22(m,3H),7.10–6.85(m,1H),6.78(d ,J=6.9Hz,1H),6.42(d,J=8.9Hz,1H),4.32–4.22(m,2H),3.32(s,3H),2.11-2.06(m,2H),1.91–1.78(m,2H),1.54–1.44(m,2H).

[0922] Example 96

[0923] 1. Synthesis of compound a

[0924] Sodium dichlorofluoroacetate (36.3 g, 237.9 mmol) was added dropwise to a stirred solution of methyl 1H-imidazolium-4-carboxylate (20 g, 158.6 mmol) and cesium carbonate (103.3 g, 317.2 mmol) in N,N-dimethylformamide (400 mL) under air at room temperature. The resulting mixture was stirred at 100 °C for 4 hours under air. The desired product was detected by liquid chromatography-mass spectrometry (LC-MS). The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water at a gradient of 10% to 30% for 30 minutes; detector, 254 nm UV, yielding methyl 1-(difluoromethyl)imidazolium-4-carboxylate (5.8 g, 20.77% yield, 95% purity) as a yellow solid.

[0925] LCMS(ESI,m / z): [M+H] + =177.15

[0926] 2. Synthesis of compound b

[0927] A mixture of methyl 1-(difluoromethyl)imidazolium-4-carboxylate (2.8 g, 15.7 mmol) and lithium hydroxide hydrate (1.3 g, 30.03 mmol) was placed in 20 mL of water and stirred at 60 °C for 4 hours in air. The desired product was detected by liquid chromatography-mass spectrometry (LC-MS). The mixture was acidified to pH 2 with 2 mol / L hydrochloric acid. The resulting mixture was concentrated under reduced pressure to give a white solid, 1-(difluoromethyl)imidazolium-4-carboxylic acid (2.5 g, crude product).

[0928] LCMS(ESI,m / z): [M+H] + =163.15

[0929] 3. Synthesis of compound c

[0930] To a stirred solution of 1-(difluoromethyl)imidazol-4-carboxylic acid (2.5 g, 15.4 mmol) and 6-chloropyridin-3-amine (2.0 g, 15.4 mmol) in dimethylformamide (25 mL), HATU (8.8 g, 23.1 mmol) and diisopropylethylamine (6.0 g, 46.3 mmol) were added fractionally under air at room temperature. The resulting mixture was stirred at 60 °C for 2 h under air. The desired product was detected by liquid chromatography-mass spectrometry. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water, 10% to 50% gradient, 30 min; detector, 254 nm UV, yielding N-(6-chloropyridin-3-yl)-1-(difluoromethyl)imidazol-4-carboxamide (2 g, 47.56% yield) as a white solid.

[0931] LCMS(ESI,m / z): [M+H] + =273.15

[0932] 4. Synthesis of compound d

[0933] Iodimazole-4-carboxamide (1.5 g, 5.5 mmol) and potassium tert-butoxide (1.9 g, 16.5 mmol) in N,N-dimethylformamide (15 mL) were added dropwise to a stirred solution at 0 °C under air. The resulting mixture was stirred at room temperature under air for 2 h. The desired product was detected by liquid chromatography-mass spectrometry (LC-MS). The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water, 10% to 40% gradient, 30 min; detector, 254 nm UV, yielding N-(6-chloropyridin-3-yl)-1-(difluoromethyl)-N-methylimidazolium-4-carboxamide (960 mg, 60.87% yield) as a yellow solid.

[0934] LCMS(ESI,m / z): [M+H] + =287.20

[0935] 5. Synthesis of Compound 161

[0936] To a stirred solution of N-(6-chloropyridin-3-yl)-1-(difluoromethyl)-N-methylimidazolium-4-carboxamide (60 mg, 0.2 mmol) and (1S,3S)-N1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclopentane-1,3-diamine (51.1 mg, 0.2 mmol) in dioxane, add (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazolium-2-ylmethylene]dichloro(2-methylpyridinium)palladium (17.6 mg, 0.02 mmol) and cesium carbonate (204.6 mg, 0.6 mmol) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 90 °C. The mixture was filtered, and the filter cake was washed with methyl cyanide. The filtrate was concentrated under reduced pressure. The crude product (mg) was purified by preparative high performance liquid chromatography to obtain N-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-(difluoromethyl)-N-methylimidazol-4-carboxamide (12.6 mg).

[0937] LCMS(ESI,m / z): [M+H] + =495.35

[0938] 1 H NMR (400MHz, DMSO-d6) δ8.23(s,2H),8.09–7.55(m,5H),7.46(d,J=7.2Hz,1H),7.27(dd,J=8.9,2.6Hz,1H),6.67(d,J=6. 9Hz,1H),6.42(d,J=8.8Hz,1H),4.26–4.21(m,2H),3.25(s,3H),2.13–2.06(m,2H),1.91–1.84(m,2H),1.62–1.38(m,2H).

[0939] Example 97

[0940] 1. Synthesis of compound a

[0941] Under a nitrogen atmosphere, iodomethane (5.7 g, 40.4 mmol) was added fractionally to a solution of 2-(6-chloropyridin-3-yl)-1-(2,5-dihydropyrrolo-1-yl)acetone (3.0 g, 13.5 mmol) and potassium tert-butoxide (4.5 g, 40.4 mmol) in N,N-dimethylformamide (30 mL) at room temperature. The resulting mixture was stirred for 1 hour at room temperature. The desired product was detected by LC-MS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid column chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water (containing 0.1% formic acid), 10% to 50% gradient, 10 min; detector, UV 254 nm. 2-(6-chloropyridin-3-yl)-1-(2,5-dihydropyrrolo-1-yl)prop-1-one (2.0 g, crude product) was obtained as a white solid.

[0942] LCMS(ESI,m / z): [M+H] + =237.20

[0943] 2. Synthesis of compound b

[0944] To a stirred solution of 2-(6-chloropyridin-3-yl)-1-(2,5-dihydropyrrolo-1-yl)prop-1-one (500 mg, 2.1 mmol) and (1S,3S)-N1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclopentane-1,3-diamine (515.9 mg, 2.1 mmol) in tetrahydrofuran (5 mL), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (167.8 mg, 0.2 mmol) and sodium tert-butoxide (812.0 mg, 8.4 mmol) was added fractionally at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 2 hours. The mixture was filtered, and the filter cake was washed with acetonitrile. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with petroleum ether / ethyl acetate (1:1) to give 2-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-(2,5-dihydropyrrolo-1-yl)prop-1-one (621 mg, crude product) as a white solid.

[0945] LCMS(ESI,m / z): [M+H] + =445.35

[0946] 3. Synthesis of compound c

[0947] To a solution of 2-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-(2,5-dihydropyrrolo-1-yl)prop-1-one (300 mg, 0.7 mmol) in dichloromethane (5 mL), manganese dioxide (3.5 g, 40.5 mmol) was added in portions under air at room temperature. The resulting mixture was stirred overnight at room temperature. The mixture was filtered, and the filter cake was washed with MeCN. The filtrate was concentrated under reduced pressure. The crude product (mg) was purified by Prep-HPLC under the following conditions (column: XBridge BEH C18 5 μm, 30 × 150 mm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient (B%): from 40% B to 55% B over 7 min; wavelength: 254 nm / 220 nm; RT1 (min): 7.17) to give 2-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-(pyrrolo-1-yl)prop-1-one (140 mg, 46.88% yield), as a brown oil.

[0948] LCMS(ESI,m / z): [M+H] + =443.35

[0949] 4. Synthesis of Compound 171

[0950] The crude product (120 mg) was purified by preparative high-performance liquid chromatography (Prep-HPLC) under the following conditions (column: CHIRALPAK IH, 3.0 × 50 mm, 3 μm; mobile phase A: carbon dioxide; mobile phase B: methanol: dichloromethane = 1:1 (0.1% 7M ammonia-methanol); flow rate: 90 mL / min; gradient (B%): isocratic 20% B; column temperature (°C): 35; column pressure (bar): 100; detection wavelength: 254 nm; RT1 (min): 4.78; RT2 (min): 5.3; injection solvent: methanol; injection volume: 0.2 mL) to obtain (2R)-2-[6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl]-1-(pyrrolo-1-yl)prop-1-one (5.6 mg).

[0951] Retention time: Rt = 1.086 min;

[0952] LCMS(ESI,m / z): [M+H] + =443.20

[0953] 1H NMR(400MHz,DMSO-d6)δ8.22(s,2H),7.99(d,J=2.5Hz,1H),7.52–7.47(m,2H ),7.44(d,J=7.1Hz,1H),7.33(dd,J=8.6,2.5Hz,1H),7.10–6.95(m,1H),6.68 –6.38(m,2H),6.29–6.24(m,2H),4.55(q,J=6.8Hz,1H),4.31–4.16(m,2H),2. 13–2.01(m,2H),1.91–1.74(m,2H),1.55–1.43(m,2H),1.40(d,J=6.8Hz,3H).

[0954] Example 98

[0955] 1. Synthesis of Compound 172

[0956] The crude product (120 mg) was purified by preparative high-performance liquid chromatography (Prep-HPLC) under the following conditions (column: CHIRALPAK IH, 3.0 × 50 mm, 3 μm; mobile phase A: carbon dioxide; mobile phase B: methanol: dichloromethane = 1:1 (0.1% 7M ammonia-methanol); flow rate: 90 mL / min; gradient (B%): constant 20% B; column temperature (°C): 35; column pressure (bar): 100; detection wavelength: 254 nm; RT1 (min): 4.78; RT2 (min): 5.3; injection solvent: methanol; injection volume: 0.2 mL) to obtain (2S)-2-[6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl]-1-(pyrrolo-1-yl)prop-1-one (8.5 mg).

[0957] Retention time: Rt = 1.232 min;

[0958] LCMS(ESI,m / z): [M+H] + =443.15

[0959] 1H NMR(400MHz,DMSO-d6)δ8.22(s,2H),7.99(d,J=2.5Hz,1H),7.52–7.47(m,2H ),7.44(d,J=7.1Hz,1H),7.33(dd,J=8.6,2.5Hz,1H),7.10–6.95(m,1H),6.68 –6.38(m,2H),6.29–6.24(m,2H),4.55(q,J=6.8Hz,1H),4.31–4.16(m,2H),2. 13–2.01(m,2H),1.91–1.74(m,2H),1.55–1.43(m,2H),1.40(d,J=6.8Hz,3H).

[0960] Example 99

[0961] 1. Synthesis of Compound 183

[0962] To a solution of (6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)acetic acid (100 mg, 0.2 mmol) and 2,3-dihydro-1H-pyrrolo[3,2-C]pyridine (34 mg, 0.2 mmol) in dichloromethane (1 mL), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (150 mg, 0.3 mmol) and N,N-diisopropylethylamine (102 mg, 0.7 mmol) were added. The resulting mixture was stirred at room temperature in air for 2 hours. The mixture was then concentrated under reduced pressure. The product was purified by flash chromatography to obtain 2-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-{2H,3H-pyrrolo[3,2-c]pyridin-1-yl} acetone (13.8 mg).

[0963] LCMS(ESI,m / z): [M+H] + =482.20

[0964] 1H NMR (400MHz, DMSO-d6) δ8.37(d,J=1.0Hz,1H),8.29(d,J=5.4Hz,1H),8.23(s ,2H),7.84(t,J=3.6Hz,2H),7.46(d,J=7.2Hz,1H),7.27(dd,J=8.6,2.4Hz,1 H),7.10–6.95(m,1H),6.52–6.37(m,2H),4.38–4.10(m,4H),3.67(s,2H),3. 20(t,J=8.6Hz,2H),2.24–2.02(m,2H),1.97–1.77(m,2H),1.67–1.40(m,2H).

[0965] Example 100

[0966] 1. Synthesis of Compound 186

[0967] To a solution of (100 mg, 0.2 mmol) acetic acid and benzmorpholine (35 mg, 0.2 mmol) in dichloromethane (1 mL), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (150 mg, 0.3 mmol) and N,N-diisopropylethylamine (102 mg, 0.7 mmol) were added at room temperature and air. The resulting mixture was stirred at room temperature and air for 2 hours. The mixture was then concentrated under reduced pressure. The product was purified by flash chromatography to obtain 2-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-(2,3-dihydro-1,4-benzoxazin-4-yl) acetone (11.4 mg).

[0968] LCMS(ESI,m / z): [M+H] + =497.25

[0969] 1 H NMR(400MHz, DMSO-d6)δ8.23(s,2H),7.78(s,2H),7.45(d,J=7.2Hz,1H),7.28–6.74(m,5H),6.48–6.35(m,2H) ,4.37–4.13(m,4H),4.00–3.83(m,2H),3.76(s,2H),2.11–2.01(m,2H),1.85–1.72(m,2H),1.62–1.32(m,2H).

[0970] Example 101

[0971] 1. Synthesis of compound a

[0972] A solution of 1-(2,5-dihydropyrrolo-1-yl)-2-(6-{[(1S,3S)-3-{[5-(trichloromethyl)-1,2,4-oxadiazol-3-yl]amino}cyclopentyl]amino}pyridin-3-yl) acetone (410 mg, 0.8 mmol), aminocyclopropane (173 mg, 3.0 mmol), and DBU (476 mg, 3.1 mmol) in dimethyl sulfoxide (5 mL) was stirred in air at room temperature for 3 hours. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile / water (0.1% formic acid), gradient from 10% to 50% over 20 minutes; detector, UV 254 nm, yielding 2-(6-{[(1S,3S)-3-{[5-(cyclopropylamino)-1,2,4-oxadiazol-3-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-(2,5-dihydropyrrole-1-yl)acetone (200 mg, 56.20% yield) as a grayish-white solid.

[0973] LCMS(ESI,m / z): [M+H] + =410.40

[0974] 2. Synthesis of compound 97-17-1

[0975] A solution of 2-(6-{[(1S,3S)-3-{[5-(cyclopropylamino)-1,2,4-oxadiazol-3-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-(2,5-dihydropyrrolo-1-yl)acetone (210 mg, 0.5 mmol) and manganese dioxide (2.67 g, 30.7 mmol) in dichloromethane (2 mL) was stirred in air at room temperature for 24 hours. The resulting mixture was filtered, and the filter cake was washed with dichloromethane. The filtrate was concentrated under reduced pressure. Column: YMC-Actus Triart C18 ExRS 5 μm, 30 mm × 150 mm; Mobile phase A: water (10 mmol / L ammonium bicarbonate + 0.1% ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient (B%): from 17% B to 52% B over 10 min; wavelength: 254 nm / 220 nm; RT1 (min): 5.98 / 9.08, yielding 2-(6-{[(1S,3S)-3-{[5-(cyclopropylamino)-1,2,4-oxadiazol-3-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-(pyrrolo-1-yl)acetone (8.0 mg).

[0976] LCMS(ESI,m / z):[M+H] + =408.20

[0977] 1 H NMR (400MHz, DMSO-d6) δ8.07(d,J=2.5Hz,1H),7.90(d,J=2.4Hz,1H),7.52(t,J=2.3H z,2H),7.30(dd,J=8.6,2.4Hz,1H),6.47(d,J=6.9Hz,1H),6.43–6.37(m,2H),6.35–6 .29(m,2H),4.20(q,J=6.7Hz,1H),4.12(s,2H),3.79(q,J=6.6Hz,1H),2.57–2.51(m, 1H),2.04–1.92(m,2H),1.88–1.81(m,1H),1.74–166(m,1H),1.55–1.38(m,2H),0.65 -0.60(m,2H),0.55–0.44(m,2H).

[0978] Example 102

[0979] 1. Synthesis of compound a

[0980] EDCI (2.1 g, 13.3 mmol) was added fractionally to a stirred solution of 1,3-oxazol-2-carboxylic acid (1.0 g, 8.8 mmol) and 6-chloropyridin-3-amine (1.1 g, 8.8 mmol) in dichloromethane (10 mL) at room temperature under air. The resulting mixture was stirred at room temperature for 2 hours. The desired product was detected by liquid chromatography-mass spectrometry. The resulting mixture was filtered, and the filter cake was washed with acetonitrile. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water, 10% to 50% gradient over 10 min; detector, UV 254 nm. N-(6-chloropyridin-3-yl)-1,3-oxazol-2-carboxamide (700 mg, 35.40% yield) was given as a white solid.

[0981] LCMS(ESI,m / z): [M+H] + =224.15

[0982] 2. Synthesis of compound b

[0983] To a stirred solution of N-(6-chloropyridin-3-yl)-1,3-oxazol-2-carboxamide (700 mg, 3.1 mmol) and potassium tert-butoxide (1.1 g, 9.4 mmol) in N,N-dimethylformamide (10 mL), iodomethane (1.3 g, 9.4 mmol) was added in portions under air at room temperature. The resulting mixture was stirred for 2 hours at room temperature. The mixture was filtered, and the filter cake was washed with acetonitrile. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water, gradient from 10% to 50% over 10 minutes; detector, UV 254 nm. N-(6-chloropyridin-3-yl)-N-methyl-1,3-oxazol-2-carboxamide (300 mg, 40.33% yield) was given as a white solid.

[0984] LCMS(ESI,m / z): [M+H] + =238.15

[0985] 3. Synthesis of Compound 179

[0986] To a stirred solution of 2-methylpyridine-1,3-oxazol-2-carboxamide-N-(6-chloropyridin-3-yl)-N-methyl (200 mg, 0.8 mmol) and (1S,3S)-N1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclopentane-1,3-diamine (205.5 mg, 0.8 mmol) in dioxane (2 mL), (SP-4-1)-1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene palladium dichloride (70.7 mg, 0.08 mmol) and cesium carbonate (822.6 mg, 2.5 mmol) were added fractionally at room temperature under a nitrogen atmosphere for 200 mg / mL. The resulting mixture was stirred overnight at 90 °C. The mixture was filtered, and the filter cake was washed with acetonitrile. The filtrate was concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography under the following conditions to obtain N-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-N-methyl-1,3-oxazol-2-carboxamide (8.5 mg).

[0987] LCMS(ESI,m / z): [M+H] + =446.35

[0988] 1H NMR (400MHz, DMSO-d6) δ8.23(s,2H),8.10(s,1H),7.74(d,J=2.7Hz,1H),7.45(d,J=7.2Hz,1H),7.31(dd,J=8.8,2.7Hz,1H),7.25–6.85(m, 2H),6.76(d,J=6.8Hz,1H),6.40(d,J=8.9Hz,1H),4.31–4.19(m,2H),3.28(s,3H),2.11–2.05(m,2H),1.90–1.77(m,2H),1.53–1.43(m,2H).

[0989] Example 103

[0990] 1. Synthesis of compound a

[0991] A solution of ethyl 5-methyl-1,3-oxazol-2-carboxylic acid (4.0 g, 25.7 mmol) and lithium hydroxide (3.0 g, 128.9 mmol) in methanol (40 mL) and water (4 mL) was stirred for 2 hours at room temperature under air. The mixture was acidified to pH 2 with hydrochloric acid. The resulting mixture was concentrated under reduced pressure to give 5-methyl-1,3-oxazol-2-carboxylic acid (4.0 g, crude product) as a pink solid.

[0992] LCMS(ESI,m / z): [M+H] + =128.10

[0993] 2. Synthesis of compound b

[0994] To a solution of 5-methyl-1,3-oxazol-2-carboxylic acid (4.0 g, 31.4 mmol) and 6-chloropyridin-3-amine (4.0 g, 31.4 mmol) in N,N-dimethylformamide (40 mL), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (17.9 g, 47.2 mmol) and N,N-diisopropylethylamine (12.2 g, 94.4 mmol) were added at room temperature and air. The resulting mixture was stirred at room temperature and air for 2 hours. The mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. Purification was performed by reversed-phase flash chromatography under the following conditions: C18 silica gel column; mobile phase: acetonitrile and water (10 mmol / L NH4HCO3), gradient 10%–50%, for 15 min; UV detector: 254 nm. The resulting N-(6-chloropyridin-3-yl)-5-methyl-1,3-oxazol-2-carboxamide (2.1 g, yield 28.08%) was a grayish-white solid.

[0995] LCMS(ESI,m / z): [M+H] + =238.05

[0996] 3. Synthesis of compound c

[0997] A solution of N-(6-chloropyridin-3-yl)-5-methyl-1,3-oxazol-2-carboxamide (1.0 g, 4.2 mmol), potassium tert-butoxide (1.4 g, 12.6 mmol), and methyl iodide (11.9 g, 84.1 mmol) in N,N-dimethylformamide (20 mL) was stirred in air at room temperature for 2 hours. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (2 / 1) to give N-(6-chloropyridin-3-yl)-N,5-dimethyl-1,3-oxazol-2-carboxamide (350 mg, 33.05% yield) as a pale pink solid.

[0998] LCMS(ESI,m / z): [M+H] + =252.10

[0999] 4. Synthesis of Compound 180

[1000] A solution of N-(6-chloropyridin-3-yl)-N,5-dimethyl-1,3-oxazol-2-carboxamide (100 mg, 0.3 mmol), (1S,3S)-N1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclopentane-1,3-diamine (97 mg, 0.3 mmol), cesium carbonate (388 mg, 1.1 mmol), and (SP-4-1)-[1,3-Bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylmethylene]dichloro(2-methylpyridine)palladium (1612891-29-8, 33 mg, 0.04 mmol) in 1,4-dioxane (1 mL) was stirred overnight at 90 °C under a nitrogen atmosphere. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure. Column chromatography: Xselect CSH C18 5 μm, 30 mm × 150 mm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient (B%): from 10% B to 28% B over 7 min; wavelength: 254 nm / 220 nm; RT1 (min): 7.55, yielding N-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-N,5-dimethyl-1,3-oxazol-2-carboxamide (13.6 mg).

[1001] LCMS(ESI,m / z):[M+H] + =460.20

[1002] 1 H NMR (400MHz, DMSO-d6) δ8.23(s,2H),7.74(d,J=2.7Hz,1H),7.46(d,J=7.2Hz,1H),7.30(dd,J=8.8,2.7Hz,1H),7.24–6.79(m,2H),6.74(d, J=6.9Hz,1H),6.41(d,J=8.9Hz,1H),4.27–4.06(m,2H),3.26(s,3H),2.23(s,3H),2.09–1.95(m,2H),1.84–172(m,2H),1.67–1.35(m,2H).

[1003] Example 104

[1004] 1. Synthesis of compound a

[1005] A solution of ethyl 4-methyl-1,3-oxazol-2-carboxylic acid (2.9 g, 18.6 mmol) and lithium hydroxide (2.2 g, 93.4 mmol) in methanol (30 mL) and water (3 mL) was stirred for 3 hours at room temperature under air. The resulting mixture was concentrated under reduced pressure to give 4-methyl-1,3-oxazol-2-carboxylic acid (1.8 g, crude product) as a white solid.

[1006] LCMS(ESI,m / z): [M+H] + =128.10

[1007] 2. Synthesis of compound b

[1008] To a solution of 4-methyl-1,3-oxazol-2-carboxylic acid (1.8 g, 14.1 mmol) and 6-chloropyridin-3-amine (1.8 g, 14.1 mmol) in N,N-dimethylformamide (20 mL), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (8.0 g, 21.2 mmol) and N,N-diisopropylethylamine (5.4 g, 42.4 mmol) were added at room temperature and air. The resulting mixture was stirred at room temperature for 3 hours in air. The mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. Purification was performed by reversed-phase flash chromatography under the following conditions: C18 silica gel column; mobile phase: acetonitrile and water (0.1% NH3·H2O), gradient 10%–50%, for 10 min; UV detector: 254 nm. N-(6-chloropyridin-3-yl)-4-methyl-1,3-oxazol-2-carboxamide (1.5 g, yield 40.11%) was obtained as a pale yellow solid.

[1009] LCMS(ESI,m / z): [M+H] + =238.10

[1010] 3. Synthesis of compound c

[1011] A solution of N-(6-chloropyridin-3-yl)-4-methyl-1,3-oxazol-2-carboxamide (500 mg, 2.1 mmol), potassium tert-butoxide (708 mg, 6.3 mmol), and methyl iodide (1493 mg, 10.5 mmol) in N,N-dimethylformamide (5 mL) was stirred in air at room temperature for 2 hours. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (2 / 1) to give N-(6-chloropyridin-3-yl)-N,4-dimethyl-1,3-oxazol-2-carboxamide (160 mg, 30.22% yield) as a grayish-white solid.

[1012] LCMS(ESI,m / z): [M+H] + =252.10

[1013] 4. Synthesis of Compound 182

[1014] A solution of N-(6-chloropyridin-3-yl)-N,4-dimethyl-1,3-oxazol-2-carboxamide (100 mg, 0.3 mmol), (1S,3S)-N1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclopentane-1,3-diamine (97 mg, 0.3 mmol), cesium carbonate (388 mg, 1.1 mmol), and 1 mL of 1,4-dioxane in the form of 3-chloropyridine;{1,3-bis[2,6-bis(hept-4-yl)phenyl]-4,5-dichloro-2,3-dihydro-1H-imidazol-2-yl}palladium dichlorodichloro(1814936-54-3, 38 mg, 0.04 mmol) was stirred overnight at 90 °C under a nitrogen atmosphere. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure. Column: Xselect CSH C18 5 μm, 30 mm × 150 mm; Mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; Flow rate: 60 mL / min; Gradient (B%): from 13% B to 25% B over 7 min; Detection wavelength: 254 nm / 220 nm; Retention time 1 (min): 7.58, yielding N-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-N,4-dimethyl-1,3-oxazol-2-carboxamide (15.0 mg).

[1015] LCMS(ESI,m / z):[M+H] + =460.20

[1016] 1 H NMR(400MHz, DMSO-d6)δ8.23(s,2H),7.87–7.60(m,2H),7.45(d,J=7.2Hz,1H),7.30(dd,J=8.8,2.7Hz,1H),7.30–6.80(m,1H),6.7 5(d,J=6.9Hz,1H),6.41(d,J=8.9Hz,1H),4.25–4.16(m,2H),3.27(s,3H),2.24–1.92(m,5H),1.83–1.62(m,2H),1.48–1.28(m,2H).

[1017] Example 105

[1018] 1. Synthesis of compound a

[1019] To a stirred solution of 6-chloropyridin-3-amine (1.0 g, 7.8 mmol) and diisopropylethylamine (3.0 g, 23.3 mmol) in dichloromethane (10 mL), 3-fluorobenzoyl chloride (1.2 g, 7.8 mmol) was added in portions under air at room temperature. The resulting mixture was stirred for 2 hours at room temperature. The mixture was extracted with dichloromethane. The combined organic layers were washed with water and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give N-(6-chloropyridin-3-yl)-3-fluorobenzamide (1.7 g, crude product) as a brownish-yellow solid.

[1020] LCMS(ESI,m / z): [M+H] + =251.15

[1021] 2. Synthesis of compound b

[1022] NaH (73.7 mg, 3.1 mmol) was added in portions to a stirred solution of N-(6-chloropyridin-3-yl)-3-fluorobenzamide (700 mg, 2.8 mmol) in DMF (10 mL) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for another 30 min. MeI (436.0 mg, 3.1 mmol) was added dropwise to the mixture at 0 °C over 1 min. The resulting mixture was stirred at room temperature for another 1 h. The reaction was terminated by adding ice water (20 mL) at 0 °C. The resulting mixture was extracted with ethyl acetate. The organic layers were combined, washed with water, and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water, 10% to 50% gradient, 10 min; detector, UV 254 nm. N-(6-chloropyridin-3-yl)-3-fluoro-N-methylbenzamide (500 mg, 67.65% yield) was obtained as a brownish-yellow solid.

[1023] LCMS(ESI,m / z): [M+H] + =265.10

[1024] 3. Synthesis of Compound 187

[1025] To a stirred solution of 4-methyl-2-(6-chloro-3-pyridyl)-3-fluoro-N-methylbenzamide (400 mg, 1.5 mmol) and (1S,3S)-N1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclopentane-1,3-diamine (369.1 mg, 1.5 mmol) in 4 mL of dioxane, under a nitrogen atmosphere at room temperature, (SP-4-1)-1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazolium-2-ylidene palladium dichloride (127.0 mg, 0.2 mmol) and cesium carbonate (1477.2 mg, 4.5 mmol) were added in portions of (SP-4-1)-1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazolium-2-ylidene palladium dichloride (127.0 mg, 0.2 mmol) and (1477.2 mg, 4.5 mmol) to the mixture, which was stirred overnight at 90 °C. The mixture was filtered, and the filter cake was washed with acetonitrile. The filtrate was concentrated under reduced pressure. The crude product (mg) was purified by preparative high performance liquid chromatography to obtain N-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-3-fluoro-N-methylbenzamide (7.0 mg).

[1026] LCMS(ESI,m / z): [M+H] + =473.30

[1027] 1 H NMR (400MHz, DMSO-d6) δ8.22(s,2H),7.69(s,1H),7.43(d,J=7.2Hz,1H),7.37–7.26(m,2H),7.22–6.84(m,4H),6.68(d,J=6 .9Hz,1H),6.35(d,J=8.9Hz,1H),4.35–4.10(m,2H),3.27(s,3H),2.10–2.02(m,2H),1.87–1.72(m,2H),1.54–1.35(m,2H).

[1028] Example 106

[1029] 1. Synthesis of compound a

[1030] Potassium carbonate (1.3 g, 9.1 mmol) was added fractionally to a stirred solution of 2,4-dichloro-5-hydroxypyrimidine (500 mg, 3.0 mmol) and 2-bromoethanol (378.8 mg, 3.0 mmol) in N,N-dimethylformamide (1 mL) at room temperature under air. The resulting mixture was stirred at 100 °C for 1 hour. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water, 10% to 50% gradient, 10 min; detector, 254 nm UV. This yielded a yellow solid, 2-chloro-6H,7H-[1,4]dioxane[2,3-d]pyrimidine (120 mg, 22.9% yield).

[1031] LCMS(ESI,m / z): [M+H] + =173.15

[1032] 2. Synthesis of compound b

[1033] To a stirred solution of 2-chloro-6H,7H-[1,4]dioxanebutano[2,3-d]pyrimidine (70 mg, 0.4 mmol) and N-(6-{[(1S,3S)-3-aminocyclopentyl]amino}pyridin-3-yl)-N,1-dimethylimidazolium-4-carboxamide (127.5 mg, 0.4 mmol) in DMSO (1.5 mL), N-(2,6-dimethylphenyl)-6-hydroxypyridine-2-carboxamide (5.9 mg, 0.02 mmol), copper iodide (3.1 mg, 0.02 mmol), and potassium carbonate (112.1 mg, 0.8 mmol) were added in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 110 °C for 2 hours. The mixture was filtered, and the filter cake was washed with methyl cyanide. The filtrate was concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography to obtain N-(6-{[(1S,3S)-3-{6H,7H-[1,4]dioxanebutano[2,3-d]pyrimidin-2-ylamino}cyclopentyl]amino}pyridin-3-yl)-N,1-dimethylimidazol-4-carboxamide (8.9 mg).

[1034] LCMS(ESI,m / z): [M+H] + =451.25

[1035] 1H NMR (400MHz, DMSO-d6) δ7.83(s,1H),7.72(s,1H),7.50–7.12(m,3H),6.74(d,J=7.2Hz,1H),6.59(d,J=6.8Hz,1H),6.41(d,J=8.8 Hz,1H),4.45–4.36(m,2H),4.27–4.11(m,4H),3.57(s,3H),3.27(s,3H),2.10–2.0(m,2H),1.87–1.75(m,2H),1.51–1.38(m,2H).

[1036] Example 107

[1037] 1. Synthesis of compound a

[1038] To a solution of 3-isoxazolecarboxylic acid (3.0 g, 26.5 mmol) and 6-chloropyridin-3-amine (3.4 g, 26.5 mmol) in N,N-dimethylformamide (50 mL), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (15.1 g, 39.7 mmol) and N,N-diisopropylethylamine (10.2 g, 79.5 mmol) were added at room temperature and air. The resulting mixture was stirred at room temperature and air for 2 hours. The mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. Purification was performed by reversed-phase flash chromatography under the following conditions: C18 silica gel column; mobile phase: acetonitrile and water (10 mmol / L NH4HCO3), gradient 10%–50%, for 15 min; UV detector: 254 nm. The resulting N-(6-chloropyridin-3-yl)-1,2-oxazol-3-carboxamide (2.5 g, yield 42.14%) was a light orange solid.

[1039] LCMS(ESI,m / z): [M+H] + =224.10

[1040] 2. Synthesis of compound b

[1041] A solution of N-(6-chloropyridin-3-yl)-1,2-oxazol-3-carboxamide (500 mg, 2.2 mmol) in N,N-dimethylformamide (5 mL) was stirred for 2 minutes at room temperature under air. Sodium hydride (160 mg, 6.7 mmol) was added in portions over 5 minutes at room temperature. The mixture was stirred for another 30 minutes at room temperature, followed by dropwise addition of iodomethane (952 mg, 6.7 mmol) at room temperature. The resulting mixture was stirred for another 2 hours at room temperature. The reaction was quenched with ice water at room temperature. The resulting mixture was extracted with ethyl acetate. The bound organic layer was washed with brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. Purification was performed by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (4 / 1), to give N-(6-chloropyridin-3-yl)-N-methyl-1,2-oxazol-3-carboxamide (240 mg, 45.17% yield) as a yellow solid.

[1042] LCMS(ESI,m / z): [M+H] + =238.10

[1043] 3. Synthesis of Compound 197

[1044] A solution (2 mL) of N-(6-chloropyridin-3-yl)-N-methyl-1,2-oxazol-3-carboxamide (100 mg, 0.4 mmol), (1S,3S)-N1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclopentane-1,3-diamine (102 mg, 0.4 mmol), (SP-4-1)-[1,3-Bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylmethylene]dichloro(2-methylpyridine)palladium (1612891-29-8, 35 mg, 0.04 mmol), and cesium carbonate (411 mg, 1.2 mmol) in 1,4-dioxane was stirred overnight at 90 °C under a nitrogen atmosphere. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure. Column: Xselect CSH C18 5μm, 19 mm × 250 mm; Mobile phase A: water (0.1% FA), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient (B%): from 15% B to 33% B over 7 min; wavelength: 254 nm / 220 nm; RT1 (min): 7.62, yielding N-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-N-methyl-1,2-oxazol-3-carboxamide (15.3 mg).

[1045] LCMS(ESI,m / z):[M+H] + =446.20

[1046] 1 H NMR (400MHz, DMSO-d6) δ8.84(d,J=1.7Hz,1H),8.23(s,2H),7.77(d,J=2.7Hz,1H),7.45(d,J=7.2Hz,1H),7.30(dd,J=8.9,2.7Hz,1H),7.03(t,J=7 4.0Hz,2H),6.51(d,J=1.7Hz,1H),6.39(d,J=8.9Hz,1H),4.24–4.16(m,2 H),3.29(s,3H),2.15–2.02(m,2H),1.94–1.74(m,2H),1.57–1.35(m,2H).

[1047] Example 108

[1048] 1. Synthesis of compound 97-17-110

[1049] A solution of 1-(2,5-dihydropyrrolo-1-yl)-2-(6-{[(1S,3S)-3-{[5-(trichloromethyl)-1,2,4-oxadiazol-3-yl]amino}cyclopentyl]amino}pyridin-3-yl) acetone (100 mg, 0.2 mmol), aminocyclopropane (42 mg, 0.7 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene; 1,8-diazabicyclo[5.4.0]undec-7-ene (116 mg, 0.7 mmol) in dimethyl sulfoxide (1 mL) was stirred at room temperature in air for 3 h. Chromatographic column: XBridge BEH C18 5μm, 19×250mm; mobile phase A: water (10mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25mL / min; gradient (B%): from 20% B to 30% B over 10min; wavelength: 254nm / 220nm; RT1 (min): 9.67. 2-(6-{[(1S,3S)-3-{[5-(cyclopropylamino)-1,2,4-oxadiazol-3-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-(2,5-dihydropyrrole-1-yl)acetone (6.1mg).

[1050] LCMS(ESI,m / z):[M+H] + =410.25

[1051] 1H NMR (400MHz, DMSO-d6) δ8.07(d,J=2.5Hz,1H),7.80(d,J=2.3Hz,1H),7.23(dd,J=8.6,2.4Hz, 1H),6.44–6.32(m,3H),5.90(s,2H),4.31(dd,J=5.3,2.8Hz,2H),4.20(q,J=6.7Hz,1H),4.06 (t,J=4.0Hz,2H),3.79(q,J=6.6Hz,1H),3.43(s,2H),2.57–2.50(m,1H),2.11–1.98(m,2H),1 .88–1.80(m,1H),1.73–1.64(m,1H),1.57–1.32(m,2H),0.65–0.59(m,2H),0.55–0.43(m,2H).

[1052] Example 109

[1053] 1. Synthesis of compound 97-17-1

[1054] A solution of 2-(6-{[(1S,3S)-3-{[5-(cyclopropylamino)-1,2,4-oxadiazol-3-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-(2,5-dihydropyrrolo-1-yl)acetone (600 mg, 1.4 mmol) and manganese dioxide (7.6 g, 87.9 mmol) in dichloromethane (15 mL) was stirred overnight in air at room temperature. The resulting mixture was filtered, and the filter cake was washed with dichloromethane. The filtrate was concentrated under reduced pressure. Chromatographic column: XBridge BEH C18 5μm, 30mm×150mm; mobile phase A: water (10mmol / L ammonium bicarbonate + 0.1% ammonia), mobile phase B: acetonitrile; flow rate: 60mL / min; gradient (B%): from 15% B to 50% B over 10min; wavelength: 254nm / 220nm; RT1 (min): 6.13 / 8.85, yielding 2-(6-{[(1S,3S)-3-{[5-(cyclopropylamino)-1,2,4-oxadiazol-3-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-(pyrrolo-1-yl)acetone (30.6mg).

[1055] LCMS(ESI,m / z):[M+H] + =408.20

[1056] 1H NMR(400MHz, DMSO-d6)δ8.08(d,J=2.5Hz,1H),7.89(d,J=2.3Hz,1H),7.60–7.49(m,2H),7 .42(d,J=8.7Hz,1H),7.14–6.82(m,1H),6.55(d,J=8.8Hz,1H),6.43(d,J=6.9Hz,1H),6.36 –6.31(m,2H),4.29–4.09(m,3H),3.80–371(m,1H),2.57–250(m,1H),2.16–1.98(m,2H),1 .91–181(m,1H),1.77–168(m,1H),1.56–1.40(m,2H),0.65–060(m,2H),0.54–0.45(m,2H).

[1057] Example 110

[1058] 1. Synthesis of compound 97-17-120

[1059] A methanol (3 mL) solution of 2-(6-{[(1S,3S)-3-{[5-(cyclopropylamino)-1,2,4-oxadiazol-3-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-(2,5-dihydropyrrolo-1-yl)acetone (100 mg, 0.2 mmol) and Pd / C (10 mg) was stirred at room temperature under a hydrogen atmosphere for 1.5 h. The resulting mixture was filtered, and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure. Column: XBridge BEH C18 5μm, 19×250mm; Mobile phase A: water (10mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; Flow rate: 25mL / min; Gradient (B%): from 23% B to 28% B over 10min; Wavelength: 254nm / 220nm; RT1 (min): 8.87. 2-(6-{[(1S,3S)-3-{[5-(cyclopropylamino)-1,2,4-oxadiazol-3-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-(pyrrolidone-1-yl)acetone (7.0mg).

[1060] LCMS(ESI,m / z):[M+H] + =412.20

[1061] 1H NMR (400MHz, DMSO-d6) δ8.07(d,J=2.5Hz,1H),7.78(d,J=2.4Hz,1H),7.22(dd,J=8.5,2. 4Hz,1H),6.46–6.30(m,3H),4.19(q,J=6.7Hz,1H),3.78(q,J=6.6Hz,1H),3.46(t,J=6.8 Hz,2H),3.39(s,2H),3.27(t,J=6.8Hz,2H),2.57–2.50(m,1H),2.04–1.95(m,2H),1.91– 1.83(m,3H),1.75–1.65(m,3H),1.60–1.35(m,2H),0.65–0.60(m,2H),0.56–0.43(m,2H).

[1062] Example 111

[1063] 1. Synthesis of Compound 3

[1064] A solution of 1-(2,5-dihydropyrrolo-1-yl)-2-(6-{[(1S,3S)-3-{[5-(trichloromethyl)-1,2,4-oxadiazol-3-yl]amino}cyclopentyl]amino}pyridin-3-yl) acetone (380 mg, 0.8 mmol), 3,3-difluorocyclobutane-1-amine (301 mg, 2.8 mmol), and DBU (429 mg, 2.8 mmol) in dimethyl sulfoxide (4 mL) was stirred in air at room temperature for 3 h. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile / water (10 mmol / L ammonium bicarbonate), gradient from 30% to 60% over 10 min; detector, UV 254 nm, yielding 2-(6-{(1S,3S)-3-({5-[(3,3-difluorocyclobutyl)amino]-1,2,4-oxadiazol-3-yl}amino)cyclopentyl]aminopyridin-3-yl)-1-(2,5-dihydropyron-1-yl)acetone (150 mg, yield 40.53%) as a yellow solid.

[1065] LCMS(ESI,m / z): [M+H] + =460.20

[1066] 2. Synthesis of compound 97-17-130

[1067] A methanol (2 mL) solution of 2-(6-{[(1S,3S)-3-({5-[(3,3-difluorocyclobutyl)amino]-1,2,4-oxadiazol-3-yl}amino)cyclopentyl]amino}pyridin-3-yl)-1-(2,5-dihydropyrrole-1-yl)acetone (120 mg, 0.2 mmol) and Pd / C (12 mg) was stirred at room temperature under a hydrogen atmosphere for 1.5 h. The resulting mixture was filtered, and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure. Chromatographic column: DAICEL DCpak P4VP 3 × 25 cm, 5 μm; mobile phase A: carbon dioxide, mobile phase B: methanol:dichloromethane = 1:1 (0.1% 7M ammonia-methanol); flow rate: 90 mL / min; gradient (B%) 25%. B; Column temperature (°C): 35; Back pressure (bar): 100; Wavelength: 254nm; RT1 (min): 6.25; RT2 (min): 7.0; Total elution time (min): 8; Pressure (bar): 162; Sample solvent: Acetonitrile: Methanol = 3:1; Injection volume: 0.5mL; Number of runs: 3, yielding 2-(6-{[(1S,3S)-3-({5-[(3,3-difluorocyclobutyl)amino]-1,2,4-oxadiazol-3-yl}amino)cyclopentyl]amino}pyridin-3-yl)-1-(pyrrolidine-1-yl)acetone (12.8mg).

[1068] LCMS(ESI,m / z):[M+H] + =462.25

[1069] 1 H NMR (400MHz, DMSO-d6) δ8.35(d,J=6.3Hz,1H),7.77(d,J=2.3Hz,1H),7.25(dd,J=8.6,2.4 Hz,1H),6.52(s,1H),6.50–6.41(m,2H),4.18–4.08(m,1H),3.92–3.81(m,1H),3.78–3.69( m,1H),3.46(t,J=6.8Hz,2H),3.41(s,2H),3.27(t,J=6.9Hz,2H),3.02–2.88(m,2H),2.76 –2.55(m,2H),2.13–1.96(m,2H),1.93–1.83(m,3H),1.75–1.64(m,3H),1.55–1.35(m,2H).

[1070] Example 112

[1071] 1. Synthesis of Compound 98

[1072] To a solution of N-(3-{[(1S,3S)-3-({5-[2-(2,5-dihydropyrrolo-1-yl)-2-oxoethyl]pyridin-2-yl}amino)cyclopentyl]amino}-1,2,4-thiadiazol-5-yl)acetamide (300 mg, 0.7 mmol) in DCM (5 mL), manganese dioxide (3.66 g, 42.1 mmol) was added in portions under ambient air at room temperature. The resulting mixture was stirred at 40 °C for 2 days. The mixture was filtered, and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The crude product (150 mg) was purified by preparative HPLC to give N-(3-{[(1S,3S)-3-({5-[2-oxo-2-(pyrrolo-1-yl)ethyl]pyridin-2-yl}amino)cyclopentyl]amino}-1,2,4-thiadiazol-5-yl)acetamide (42.9 mg, 14.37% yield).

[1073] LCMS(ESI,m / z):[M+H] + =426.15

[1074] 1 H NMR (400MHz, DMSO-d6) δ12.43 (s, 1H), 7.88 (d, J = 2.3Hz, 1H), 7.51 (s, 2H), 7. 29(dd,J=8.7,2.4Hz,1H),6.92(d,J=7.0Hz,1H),6.48(d,J=6.9Hz,1H),6.42 (d,J=8.6Hz,1H),6.32(t,J=2.4Hz,2H),4.25–4.13(m,2H),4.11(d,J=7.0Hz ,2H),2.17(s,3H),2.12–2.05(m,2H),1.92–1.75(m,2H),1.55–1.39(m,2H).

[1075] Example 113

[1076] 1. Synthesis of Compound 161

[1077] To a stirred solution of 6-chloropyridin-3-yl-N-(1,1-difluoromethyl)-N-methylimidazolium-4-carboxamide (500.0 mg, 1.7 mmol) and (1S,3S)-N1-[5-(1,1-difluoromethoxy)pyrimidin-2-yl]cyclopentane-1,3-diamine (426.0 mg, 1.7 mmol) in dioxane (5 mL), under a nitrogen atmosphere at room temperature, (SP-4-1)-1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazolium-2-ylidenedichloro(2-methylpyridinium)palladium (146.5 mg, 0.2 mmol) and cesium carbonate (1704.8 mg, 5.2 mmol) were added in portions of (SP-4-1)-1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazolium-2-ylidenedichloro(2-methylpyridinium)palladium (146.5 mg, 0.2 mmol) and (1704.8 mg, 5.2 mmol) to the mixture, and stirred overnight at 90 °C. The mixture was filtered, and the filter cake was washed with acetonitrile. The filtrate was concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography under the following conditions to obtain N-(6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-1-(difluoromethyl)-N-methylimidazol-4-carboxamide (95.1 mg).

[1078] LCMS(ESI,m / z): [M+H] + =495.35

[1079] 1 H NMR (400MHz, DMSO-d6) δ8.23(s,2H),8.00(s,1H),7.73(s,2H),7.45(d,J=7.2Hz,2H),7.27(dd,J=8.9,2.6Hz,1H),7.20–6.85(m,1H), 6.67(d,J=6.9Hz,1H),6.42(d,J=8.8Hz,1H),4.33–4.21(m,2H),3.25(s,3H),2.13–2.06(m,2H),1.97–1.78(m,2H),1.58–1.40(m,2H).

[1080] Example 114

[1081] 1. Synthesis of Compound 3

[1082] A solution of 4,6-dichloropyridin-3-amine (1.0 g, 6.1 mmol) and diisopropylethylamine (1.8 g, 18.4 mmol) in DCM (10 mL) was stirred under air, and then 1-methylimidazolium-4-carboxyl chloride (887 mg, 6.135 mmol) was added in portions at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The desired product was detected by LCMS. The precipitated solid was collected by filtration and washed with methanol. N-(4,6-dichloropyridin-3-yl)-1-methylimidazolium-4-carboxamide (1.02 g, 61.33% yield) was given as a gray solid.

[1083] LCMS(ESI,m / z): [M+H] + =271.00

[1084] 2. Synthesis of Compound 4

[1085] Sodium hydride (97.4 mg, 4.1 mmol) was added in portions to a stirred solution of N-(4,6-dichloropyridin-3-yl)-1-methylimidazolium-4-carboxamide (1.0 g, 3.7 mmol) in 10 mL of DMF at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for another 30 min. Iodimethane (575.9 mg, 4.1 mmol) was added in portions to the mixture at 0 °C over 2 min. The resulting mixture was stirred at room temperature for another 2 h. The reaction was quenched with methanol at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, methanol in water, 10% to 50% gradient, 10 min; detector, UV 254 nm. N-(4,6-dichloropyridin-3-yl)-N,1-dimethylimidazol-4-carboxamide (500 mg, 47.54% yield) was obtained as a brown oil.

[1086] LCMS(ESI,m / z): [M+H] + =285.00

[1087] 3. Synthesis of Compound 188-1

[1088] To a stirred solution of 4,6-dichloropyridin-3-yl-N,N-dimethyl-4-carboximide (500 mg, 1.7 mmol) and (1S,3S)-N1-[5-(difluoromethoxy)pyrimidin-2-yl]cyclopentane-1,3-diamine (428.3 mg, 1.7 mmol) in dioxane (5 mL), (SP-4-1)-[1,3-Bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylylene]dichloro(2-methylpyridinium)palladium (147.3 mg, 0.2 mmol) and cesium carbonate (1714.0 mg, 5.3 mmol) were added in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 90 °C. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography to obtain N-(4-chloro-6-{[(1S,3S)-3-{[5-(difluoromethoxy)pyrimidin-2-yl]amino}cyclopentyl]amino}pyridin-3-yl)-N,1-dimethyl-4-carboximide (6.3 mg).

[1089] LCMS(ESI,m / z): [M+H] + =493.10

[1090] 1 H NMR (400MHz, DMSO-d6) δ8.24(s,2H),7.82(s,1H),7.47(dd,J=7.3,4.5Hz,1H),7.35(d,J=6.2Hz,2H),7.23–6.84(m,2H ),6.54(s,1H),4.33–4.26(m,2H),3.57(s,3H),3.13(s,3H),2.11–2.07(m,2H),1.93–1.81(m,2H),1.55–1.44(m,2H).

[1091] Example 115

[1092] 1. Synthesis of Compound 3

[1093] To a stirred solution of 6-chloropyridin-3-amine (2.0 g, 15.6 mmol) and 2-methyl-1,3-oxazol-4-carboxylic acid (2.0 g, 15.6 mmol) in dichloromethane (20 mL), HATU (8.9 g, 23.3 mmol) and diisopropylethylamine (8.0 g, 62.2 mmol) were added fractionally at room temperature under air. The resulting mixture was stirred for 2 h at room temperature. The desired product was detected by liquid chromatography-mass spectrometry. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (1:1), to give N-(6-chloropyridin-3-yl)-2-methyl-1,3-oxazol-4-carboxamide (2.0 g, 54.10% yield, 95% purity) as a yellow solid.

[1094] LCMS(ESI,m / z): [M+H] + =238.05

[1095] 2. Synthesis of Compound 4

[1096] To a stirred solution of N-(6-chloropyridin-3-yl)-2-methyl-1,3-oxazol-4-carboxamide (1.0 g, 4.2 mmol) and potassium tert-butoxide (1.4 g, 12.6 mmol) in N,N-dimethylformamide (10 mL), iodomethane (1.8 g, 12.6 mmol) was added fractionally under air at room temperature. The resulting mixture was stirred for 2 h at room temperature. The desired product was detected by liquid chromatography-mass spectrometry. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (1:1), to give N-(6-chloropyridin-3-yl)-N,2-dimethyl-1,3-oxazol-4-carboxamide (200 mg, 18.89% yield, 95% purity) as a yellow oil.

[1097] LCMS(ESI,m / z): [M+H] + =252.05

[1098] 3. Synthesis of Compound 196

[1099] 2-Methylpyridinepalladium (SP-4-1)-1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene dichloride (50.1 mg, 0.06 mmol) and cesium carbonate (582.6 mg, 1.8 mmol) were added in portions to a stirred solution of N-(6-chloropyridin-3-yl)-N,2-dimethyl-1,3-oxazol-4-carboxamide (150 mg, 0.6 mmol) and (1S,3S)-N1-[5-(difluoromethoxy)py...

Claims

1. The compound represented by formula (I), its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof: E2-L-E1-XAYG (I) in, A is selected from unsubstituted or arbitrarily assigned to one, two or more R. a The following groups are substituted: C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10 quinone heteroaryl; each R a They are either the same or different, and are independently selected from halogens, OH, CN, and C. 1-10 alkyl; X does not exist or is selected from single bonds, N(R) x ), S, C(R) x (R) x ); Each R x They may be the same or different, and are independently selected from H, halogens, OH, CN, and C. 1-10 Alkyl group; when X is absent, A and E1 are screwed together to form a helical ring; Y is selected from S, without substitution, or optionally by one, two, or more R. y The following groups are substituted: NH, NHC(O), NHC(O)O, -CH2NH-, -CH2CH2NH-; each R y They are either the same or different, and are independently selected from halogens, OH, CN, and C. 1-10 Alkyl; or, two Rs y The atoms connected to each other form C 3-10 cycloalkyl; E1 is selected from unsubstituted or optionally by one, two or more R... E1 The following groups are substituted: 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10 quinone heteroaryl; each R E1 They are either the same or different, and are independently selected from halogens, OH, CN, and C. 1-10 alkyl; E2 is selected from OH, unsubstituted, or optionally surrounded by one, two, or more R groups. E2 The following groups are substituted: C 1-10 Alkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10 membered heteroaryl, amino; each R E2 They are either the same or different, and are independently selected from halogens, oxometalates (=O), OH, CN, C(O)OH, C 1-10 Alkyl, Halogenated C 1-10 Alkyl, C 3-10 cycloalkyl, C 6-10 Aryl, Halogenated C 6-10 Aryl, Halogenated C 1-10 Alkoxy, C 1-10 Alkoxy-C 6-10 Aryl-C 1-10 Alkyl, C 3-10 cycloalkyl-NH-; L is selected from single bond, -N(R) L )-、-C(O)C(R L (R) L )-、-C(O)N(R L )-、-C(R L (R) L -; each R L They may be the same or different, and are independently selected from H, without substitution, or optionally by one, two, or more R. L1 The following groups are substituted: C 1-10 Alkyl, C 3- 10 cycloalkyl, C 3-10 Cycloalkenyl, C 6-10 Aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclic; each R L1 They are either the same or different, and are independently selected from halogens, oxometalates (=O), and carbon atoms. 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 1-10 Alkyl-C 3-10 cycloalkyl; Or, two Rs L The atoms connected to each other form C 3-10 cycloalkyl groups, 3-10 membered heterocyclic groups; G is selected from unsubstituted or optionally by one, two or more Rs. g The following groups are substituted: C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10 quinone heteroaryl; each R g They may be the same or different, and are independently selected from halogens, OH, CN, oxo (=O), and C. 1-10 Alkyl, C 1-10 Alkoxy, halogenated C 1-10 Alkyl, Halogenated C 1-10 Alkoxy, C 1-10 Alkyl-NH-, C 3-10 cycloalkyl-NH-, halogenated C 3-10 cycloalkyl-NH-, C 1-10 Alkyl-NHC(O)-, C 1-10 Alkyl-C(O)NH-.

2. The compound according to claim 1, its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, characterized in that, A is selected from unsubstituted or arbitrarily assigned to one, two or more R. a The following groups are substituted: C 3-8 Cycloalkyl, 5-9 membered heterocyclic groups, C 6-9 Aryl, 5-6 quinone heteroaryl; Preferably, A is selected from unsubstituted or optionally substituted by one, two or more R. a The following groups may be substituted: cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[3.1.0]hexyl, spiro[2.4]heptyl, bicyclo[3.2.0]heptyl, 2-azaspiro[3.4]octyl, phenyl, pyridyl, 2,3-dihydro-1H-indenyl; Preferably, each R a They may be the same or different, and are independently selected from halogens (e.g., F), OH, CN, C. 1-6 alkyl; Preferably, A is selected from And when X does not exist, A is selected from Preferably, A is selected from And when X does not exist, A is selected from 3. The compound, its stereoisomers, tautomers, or pharmaceutically acceptable salts according to claim 1 or 2, characterized in that, X is selected from single bonds, N(R) x ), S, C(R) x (R) x ); Each R x They are either the same or different, and are independently selected from H, OH, CN, and C. 1-6 Alkyl groups (e.g., methyl groups); Preferably, X is selected from single bonds, NH, S, (For example )、 (For example )； Preferably, Y is selected from NH, S, NHC(O), NHC(O)O, Preferably, each R y Same or different, selected independently from C 1-6 Alkyl (e.g., methyl); or, two Rs y The atoms connected to each other form C 3-6 Cycloalkyl groups (e.g., cyclopropyl); Preferably, Y is selected from NH, S, NHC(O), NHC(O)O, (For example )、 4. The compound, its stereoisomers, tautomers, or pharmaceutically acceptable salts according to any one of claims 1-3, characterized in that, E1 is selected from unsubstituted or optionally by one, two or more R... E1 The following groups are substituted: 6-9 membered heterocyclic groups, C 6-8 Aryl, 5-6 quinary heteroaryl, 9-10 quinary heteroaryl; Preferably, E1 is selected from unsubstituted or optionally substituted by one, two or more R. E1 The following groups are substituted: pyridinyl, pyridazinyl, thiazolyl, oxazolyl, phenyl, benzimidazolyl, 2,3-dihydro-1H-pyrrolo[3,2-b]pyridinyl, indolinel; Preferably, E1 is selected from Preferably, each R E1 They may be the same or different, and are independently selected from halogens (e.g., F, C). 1-6 alkyl; Preferably, E1 is selected from (For example )、 (For example )、 And when X does not exist, E1 is selected from Preferably, E2 is selected from OH, unsubstituted, or optionally substituted with one, two, or more R groups. E2 The following groups are substituted: C 1-6 Alkyl, 4-8 membered heterocyclic, 9-10 membered heterocyclic, C 6-8 Aryl, 5-6 quinary heteroaryl, 8-10 quinary heteroaryl; Preferably, E2 is selected from OH, unsubstituted, or optionally substituted with one, two, or more R groups. E2 The following groups are substituted: methyl, 1,2-dihydropyridyl, pyrrolyl, imidazole, phenyl, 2,3-dihydro-1H-imidazolyl, aziridine, aziridine-butenyl, tetrahydropyrrolyl, indolinel, Indolyl, 1H-pyrrolo[3,2-b]pyridyl, pyrazolyl, 1H-pyrrolo[2,3-b]pyridyl, 2H-indazoleyl, thiazolyl, triazolyl, dihydropyrrolyl, 1H-pyrazololo[3,4-b]pyridyl, 7H-pyrrolo[2,3-c]pyridazinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, 1H-pyrrolo[3,4-d]pyrimidinyl, indololinyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine, 6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidinyl, morpholinyl, piperazinyl, piperidinyl, amino, oxazolyl, isoxazolyl, oxadiazolyl, furanyl Preferably, each R E2 They are either the same or different, and are independently selected from halogens, oxometalates (=O), C(O)OH, CN, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-6 cycloalkyl, C 6-8 Aryl, Halogenated C 6-8 Aryl, Halogenated C 1-6 Alkoxy, C 1-6 Alkoxy-C 6-8 Aryl-C 1-6 Alkyl, C 3-6 cycloalkyl-NH-; Preferably, each R E2 They are either the same or different, and are independently selected from F, oxo(=O), C(O)OH, CN, methyl, difluoromethyl, phenyl, 4-methoxybenzyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, trifluoromethoxy, difluoromethoxy, cyclopropyl, cyclopropyl-NH-, 3-fluorophenyl, 4-fluorophenyl, 3,4-difluorophenyl; Preferably, E2 is selected from OH, methyl, difluoromethyl, trifluoromethyl, ...

5. The compound, its stereoisomers, tautomers, or pharmaceutically acceptable salts according to any one of claims 1-4, characterized in that, L is selected from single bond, -C(O)C(R) L (R) L )-、-C(O)N(R L )-、-C(R L (R) L )-; Preferably, each R L They may be the same or different, and are independently selected from H, without substitution, or optionally by one, two, or more R. L1 The following groups are substituted: C 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, C 6-8 aryl, 5-10 membered heteroaryl, 3-8 membered heterocyclic; or, two R groups L The atoms connected to each other form C 3-6 cycloalkyl groups, 3-6 membered heterocyclic groups; Preferably, each R L1 They may be the same or different, and are independently selected from halogens (e.g., F), oxo (=O), and C. 1-6 Alkyl (e.g., methyl), C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 1-6 Alkyl-C 3-6 cycloalkyl; Preferably, each R L Same or different, selected independently from C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, C 6-8 Aryl, Halogenated C 6-8 Aryl, 5-6 quinary heteroaryl, 9-10 quinary heteroaryl, C 1-6 Alkyl-5-6-membered heteroaryl, 3-6-membered heterocyclic, 3-6-membered heterocyclic-C 1-6 Alkyl, C 3-6 cycloalkyl-C 1-6 Alkyl, C 1-6 Alkyl-C 3-6 cycloalkyl-C 1-6 Alkyl; or, two Rs L The atoms bonded to them form cyclopropyl, cyclobutyl, oxacyclobutyl, cyclopentyl, and cyclohexyl groups; Preferably, each R L They may be the same or different, and are independently selected from methyl, trifluoromethyl, difluoromethyl, 3-fluorophenyl, 4-fluorophenyl, imidazolyl, triazolyl, pyrimidinyl, thiazolyl, phenyl, oxacyclobutyl, pyridinyl, indole, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, fluorophenyl, Or, two Rs L The atoms connected to each other form Preferably, L is selected from single bonds, NH, (For example )、 6. The compound, its stereoisomers, tautomers, or pharmaceutically acceptable salts according to any one of claims 1-5, characterized in that, G is selected from unsubstituted or optionally by one, two or more Rs. g The following groups are substituted: C 3-6 Cycloalkyl, 5-6 membered heterocyclic, 9-10 membered heterocyclic, C 6-8 Aryl, 5-6 quinary heteroaryl, 9-10 quinary heteroaryl; Preferably, G is selected from unsubstituted or optionally substituted by one, two or more R. g The following groups may be substituted: thiazolyl, 2-oxabicyclohexyl, phenyl, cyclopropyl, triazine, oxadiazole, oxazole, thiazolyl, triazolyl, pyrimidinyl, Preferably, G is selected from Preferably, each R g Whether the two are the same or different, they are independently selected from H, oxo (=O), and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C 3-6 cycloalkyl, C 1-6 Alkyl-NH-, C 3-6 cycloalkyl-NH-, halogenated C 3-6 cycloalkyl-NH-, C 1-6 Alkyl-NHC(O)-, C 1-6 Alkyl-C(O)NH-; Preferably, each R g They may be the same or different, and are independently selected from H, oxo (=O), methyl, ethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, cyclopropyl, Preferably, G is selected from H, 7. The compound, its stereoisomers, tautomers, or pharmaceutically acceptable salts according to any one of claims 1-6, characterized in that, The compound represented by formula (I) is selected from the following compounds: Wherein, A, X, Y, E1, E2, L, and G independently have the definitions described in any one of claims 1-6; Preferably, the compound represented by formula (I) is selected from the following compounds: Wherein, A, X, Y, E1, E2, L, and G independently have the definitions described in any one of claims 1-6; Preferably, the compound represented by formula (I) is selected from the following compounds: Among them, E1, E2, L, G, R g R L Each of them independently possesses the definition described in any one of claims 1-6; Preferably, the compound represented by formula (I) is selected from the following compounds: Among them, E2, R g R L Each of them independently possesses the definition described in any one of claims 1-6; Preferably, the compound represented by formula (I) is selected from the following compounds: Among them, E2, R g R L Each of them independently has the definition as described in any one of claims 1-6.

8. The compound, its stereoisomers, tautomers, or pharmaceutically acceptable salts according to any one of claims 1-7, characterized in that, The compound is selected from the following structures:

9. A pharmaceutical composition comprising at least one of the compounds of any one of claims 1-8, their stereoisomers, tautomers, or pharmaceutically acceptable salts thereof.

10. The use of the compound of any one of claims 1-8, its stereoisomers, tautomers or pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment and / or prevention of cardiovascular diseases; Preferably, the cardiovascular disease is selected from hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome, and coronary artery disease. Preferably, the cardiovascular disease is familial hypercholesterolemia; Preferably, the cardiovascular disease is autosomal dominant hypercholesterolemia.

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